J Cancer Res Clin Oncol DOI 10.1007/s00432-016-2136-1
REVIEW – CLINICAL ONCOLOGY
The Aurora kinase inhibitors in cancer research and therapy Jonas Cicenas1,2,3
Received: 21 January 2016 / Accepted: 18 February 2016 © Springer-Verlag Berlin Heidelberg 2016
Abstract Compounds that affect enzymatic function of kinases are valuable for the understanding of the complex biochemical processes in cells. Aurora kinases (AURKs) play a key role in the control of the mitosis. These kinases are frequently deregulated in different human cancers: overexpression, amplifications, translocations and deletions were reported in many cancer cell lines as well as patient tissues. These findings steered a rigorous hunt for smallmolecule AURK inhibitors not only for research purposes as well as for therapeutic uses. In this review, we describe a number of AURK inhibitors and their use in cancer research and/or therapy. We hope to assist researchers and clinicians in deciding which inhibitor is most appropriate for their specific purpose. The review will also provide a broad overview of the clinical studies performed with some of these inhibitors (if such studies have been performed). Keywords Aurora kinases · Protein kinases · Small-molecule inhibitors · Cancer · Cell cycle
Introduction Protein kinases are a large family of enzymes, with more than 500 members in human genome. They catalyze protein
* Jonas Cicenas
[email protected] 1
CALIPHO Group, Swiss Institute of Bioinformatics, CMU‑1, rue Michel Servet, 1211 Geneva 4, Switzerland
2
MAP Kinase Resource, Melchiorstrasse 9, 3027 Bern, Switzerland
3
Proteomics Centre, Vilnius University Institute of Biochemistry, 08662 Vilnius, Lithuania
phosphorylation, resulting in a change of protein location, interaction with other proteins or nucleic acids, enzymatic activity, stability or other features. Protein phosphorylation plays a central role in the regulation of man cellular processes, such as proliferation, differentiation, migration, apoptosis and many others. Thus, misregulation of kinases can result in prominent changes in such processes and cause pathological conditions, such as cancer. The phosphorylation of kinases themselves as well as some other proteins have been shown to be associated with prognosis in cancers, for example: Akt (Cicenas et al. 2005; Cicenas 2008), androgen receptor (Willder et al. 2013), EGFR (Cicenas 2007; Kanematsu et al. 2003), ErbB2 (Cicenas et al. 2006; DiGiovanna et al. 2005), Erk (Milde-Langosch et al. 2005; Bergqvist et al. 2006; Svensson et al. 2005), p21Cip1 (Xia et al. 2004), p27Kip1 (Clarke 2003), retinoblastoma protein (Rb) (Derenzini et al. 2007) and SchA (Cicenas et al. 2010). The Aurora kinases are the family of serine/threonine kinases, prominently involved in cell cycle where most important of their functions are attributed to the regulation of mitosis. They are involved in crucial checkpoint regulation pathways such as spindle assembly checkpoint, alignment of metaphase chromosomes and chromosomal biorientation. The first Aurora kinase was initially discovered in 1995 in a Drosophila mutant in which the loss of function of a serine–threonine kinase caused a failure of the centrosomes to separate and to form a bipolar spindle (Glover et al. 1995). There are three mammalian Aurora kinases, and although at first the nomenclature was very diverse, now they are labeled Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC) (Carpinelli and Moll 2008) (Fig. 1). They are structurally divided into three domains: N-terminal domain, a protein kinase domain and C-terminal domain. AURKAs are most conserved in their
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Fig. 1 Aurora kinases: a schematic differences between Aurora kinase family members. b Structure of AURKA in complex with MLN8054. c Structure of AURKA activation loop in complex with MLN8054 [a and b images from the RCSB PDB (www.rcsb.org). DOI: 10.2210/pdb2x81/pdb]
catalytic and C-terminal domains (A and B share 71 % identity) (Carmena and Earnshaw 2003). All three kinases are involved in slightly different, however, overlapping functions. The activity of AURKA is regulated by a several binding proteins, which either activate or inhibit the kinase as well as by several phosphorylations. It is activated by autophosphorylation at T288 upon TPX2 binding (Reboutier et al. 2012; Walter et al. 2000; Kufer et al. 2002). However, TPX2 binding occurs when AURKA is already phosphorylated at T287 (Mori et al. 2009), which seems to be achieved by autophosphorylation as well (Ferrari et al. 2005). Other autophosphorylation sites with unknown significance are T148 and S342. AJUBA, FRY and BORA are other important activating interactors of AURKA (Hirota et al. 2003; Hutterer et al. 2006; Ikeda et al. 2012). Interaction with BORA stimulates phosphorylation of PLK1 kinase (Macu˚rek et al. 2008) and phosphorylation of BORA by PLK1, resulting in its stabilization and thus stabilization of the activity of AURKA. AURKA can also be phosphorylated by PAK1 on T288 and S342 (Zhao et al. 2005), PKA on T288 (Walter et al. 2000), SRC (Ratushny et al. 2012), LIMK1 (Ritchey et al. 2012) and PKCζ (Mori et al. 2009). S51 and S89 can also be phosphorylated and together with T288 can serve as binding sites for several phosphatases, which participate in dephosphorylation and subsequent degradation of AURKA (Katayama et al. 2001; Horn et al. 2007).
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In mitosis, AURKA regulates G2/M transition of cell cycle (Marumoto et al. 2003). It regulates the microtubule organizing center (Saskova et al. 2008), mitotic spindle assembly via phosphorylation of KIF2A (Jang et al. 2009) and centrosome separation via phosphorylation of TACC1 and TACC3 (Glover et al. 1995). Other important substrates of AURKA include ARPC1B (Molli et al. 2010), CENPA (Kunitoku et al. 2003), BRCA1, LATS2, NME1, p53, KIF11, NDEL1 and TPX2 (Li and Li 2006). Just like AURKA, AURKB also needs protein–protein interactions together with phosphorylations to be activated. It forms so-called chromosomal passenger complex together with BIRC5 (survivin), CDCA8 (borealin) and INCENP (Jeyaprakash et al. 2007). Binding of AURKB to INCENP (Honda et al. 2003) causes AURKB translocation to centromeric areas of the chromosome and midzone microtubule array (Adams et al. 2000). As the enzymatic subunit of the chromosomal passenger complex, AURKB has crucial functions at the centromere regulating correct chromosome alignment and segregation during mitosis (Shuda et al. 2009; Kaitna et al. 2002). The kinase activity of AURKB is also regulated by several phosphorylations. Autophosphorylation at T232 is crucial to the binding of INCENP and activates kinase activity (Yasui et al. 2004). Another important phosphorylation, leading to activation of AURKB, is the phosphorylation of S311 by CHEK1 (Petsalaki et al. 2011). AURKB phosphorylates the other
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subunits of the chromosomal passenger complex, as well as other substrates such as KIF2C (Andrews et al. 2004), CENPA (Zeitlin et al. 2001), desmin (Kawajiri et al. 2003) and vimentin (Goto et al. 2003). AURKC is the least characterized member of the family and its function seems to be dual. On the one hand, it has been shown to have its major role in meiosis during spermatogenesis (Yang et al. 2010; PMID: Kimmins et al. 2007). On the other hand, an overlapping function with AURKB has been shown in mitosis, where AURKC regulates correct chromosome alignment and segregation, attachment of spindle microtubules to kinetochore and mitotic cytokinesis (Slattery et al. 2009; Yang et al. 2010; Sasai et al. 2004). Similarly to AURKB, AURKC interacts with the chromosomal passenger complex subunits INCENP and BIRC5 (Sasai et al. 2004; Yan et al. 2005). AURKC is known to phosphorylate TACC1 (Gabillard et al. 2011), CDCA8 (Slattery et al. 2008), CENPA (Slattery et al. 2008) and TERF2 (Spengler 2007). Many kinase inhibitors are available for the use in cancer research as well as in the targeted treatment of cancer (Gharwan and Groninger 2015). Imatinib mesylate (Gleevec)—an ABL tyrosine kinase inhibitor, was the first molecule to deliver the proof of principle that targeting an abnormal kinase responsible for tumorigenic supports the suppression of cancer (Zoubir et al. 2010). It was the first small-molecule kinase inhibitor to be approved in the clinic for the use in chronical myeloid leukemia therapy (Druker
2002). Since the success of Gleevec, many researchers in academia as well as in industry focused their research on kinase inhibitors, which inhibit kinases like EGFR, ERBB2, VEGF, BRAF, JNK and others (Jänne et al. 2009; Cicenas 2015). The first inhibitors to target cell cycle in particular were the inhibitors of cyclin-dependent protein kinases (CDKs). More than 30 of those have been developed and many tested in clinics (Cicenas and Valius 2011; Cicenas et al. 2014; Cicenas et al 2015). First smallmolecule inhibitor of AURKAs, hesperadin, was reported in 2003 (Hauf et al. 2003) and first patient was treated in 2004 with an inhibitor PHA-739358 (Carpinelli and Moll 2008). To date, many different AURK small-molecule inhibitors have been developed, which can be subdivided into two main groups: pan-Aurora inhibitors (such as AMG 900, SNS-314, CCT 137690, VX-680/MK0457, VE-465, PHA-680632) and selective inhibitors (such as hesperadin, AZD1152, GSK1070916, MLN8054, MLN8237, PF-3814735, VX-689/MK-5108, TC-A 2317, ZM 447439).
Pan‑Aurora inhibitors AMG 900 is a potent and highly selective pan-Aurora inhibitor with IC50 of 5 nM for AURKA, 4 nM for AURKB and 1 nM for AURKC (Fig. 2). It is >10-fold selective for Aurora kinases than p38α, TYK2, JNK2, MET and TIE2 (Payton et al. 2010). In preclinical studies, AMG
Fig. 2 SNS-314, AMG 900 and CCT 137690
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900-treated cells entered mitosis, but failed to properly congress chromosomes to the metaphase plate, which consequently inhibited cell proliferation and induced polyploidy. It inhibited proliferation of several tumor cell lines, including cells resistant to several chemotherapeutic agents, and was more potent than other three AURK inhibitors tested. In addition, AMG 900 showed significant antitumor activity in xenograft mouse models of breast, colon, lung, pancreatic and uterine cancers, including xenograft models that were resistant to either docetaxel or paclitaxel. AMG 900 was also used in combination with HDAC inhibitors, and they synergistically decreased cell proliferation and survival in DU-145, LNCaP, and PC3 prostate cancer cell lines compared to single-agent treatment. In DU-145 xenograftsbearing mice group treated with a combination of low-dose AMG 900 and HDAC inhibitor vorinostat, the average tumor growth rate was lower than the tumor growth rate in groups treated with low-dose AMG 900 alone or vorinostat alone (Paller et al. 2014). Combination of AMG 900 and vorinostat was also effective against medulloblastoma cell lines, reaching 100 % inhibition of colony formation. Based on its potency, selectivity, dosing flexibility and efficacy against tumor cells and tumor xenografts, AMG 900 was selected as a candidate for clinical trials (PMID: Geuns-Meyer et al. 2015). Phase I study in adult patients with advanced solid tumors showed tumor response rates for 17 patients: 13 patients with stable disease, four with progressive disease and one with recurrent ovarian cancer having 16 % tumor shrinkage. Major dose-limiting toxicities were neutropenia, thrombocytopenia and febrile neutropenia (Carducci et al. 2012). SNS-314 is a potent and selective pan-Aurora inhibitor with IC50 of 9 nM for AURKA, 31 nM for AURKB and 3 nM for AURKC (Fig. 2). It is more than fivefold selective
Fig. 3 MK-0457/VE-465 and PHA-680632
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for Aurora kinases than TRK A/B, FLT4, FMS, AXL, RAF1 and DDR2 (Oslob et al. 2008). In preclinical studies, SNS-314 had antiproliferative activity and when used with chemotherapeutic compounds showed additive antiproliferative effects with carboplatin, gemcitabine, 5-FU, daunomycin, SN-38, gemcitabine, docetaxel and vincristine (VanderPorten et al. 2009). It also potentiated the antitumor activity of docetaxel in xenografts. In the other colon cancer xenograft model study, SNS-314 showed inhibition of histone H3 phosphorylation and cell cycle progression, increase in apoptosis and nuclear size as well as tumor growth inhibition (Arbitrario et al. 2010). Anaplastic thyroid cancer cell lines develop decreasing cell growth and tumorigenicity by the SNS-314 as well (Baldini et al. 2012). CCT 137690 is a potent inhibitor of Aurora kinases with IC50 of 0.015 μM for AURKA, 0.019 μM for AURKC and 0.025 μM for AURKB (Fig. 2). It is very orally available and was shown to inhibit the growth of SW620 colon carcinoma xenografts with no detected toxicities (Bavetsias et al. 2010). CCT 137690 also had anti-proliferative activity against 13 of human cancer cell lines in dose-dependent manner, most sensitive being SW48 colon cancer line (0.005 μM) (Faisal et al. 2011). Interesting, dual FLT3Aurora inhibition seems to overcome FLT3 inhibitor resistance in AML and could be a solution to FLT3 mutations (Moore et al. 2012). In addition, it was shown that SW620 colorectal cells are sensitized to radiotherapy by CCT 137690 (Wu et al. 2014). MK-0457 (VX-680, tozasertib) is a pan-Aurora inhibitor with IC50 of 0.6 nM for AURKA, 18 nM for AURKB and 4.6 nM for AURKC (Harrington et al. 2004) (Fig. 3). Interestingly, this inhibitor is also effective against ABL1 T315I mutant, which is resistant to imatinib and dasatinib
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(Giles et al. 2007). That happens via MK-0457 binding to ABL1 in a manner that uses the substitution of isoleucine for threonine at residue 315 (Young et al. 2006). MK-0457 induced G(2)/M phase arrest and apoptosis by changing phosphorylation or expression of apoptosis-regulating proteins (Huang et al. 2008). The inhibitor also inhibited anaplastic thyroid cancer cell lines CAL-62, 8305C, 8505C, and BHT-101 proliferation, apoptosis, colony formation and cell cycle progression (Arlot-Bonnemains et al. 2008). Combination of vorinostat and MK-0457 induced apoptosis in CML cells both sensitive and resistant to imatinib in higher manner than either single agent (Dai et al. 2008). Similar results were seen with AML cell lines (Fiskus et al. 2008). Docetaxel in combination with MK-0457 had more than 10-fold greater cytotoxicity in HeyA8 and SKOV3ip1 ovarian cancer cell lines, than docetaxel alone (Lin et al. 2008). Combination with cisplatin inhibited the growth of HepG2 human liver cancer cell line (Yao et al. 2014). Combined treatment with ABT-737 and MK-0457 induced apoptosis in breast carcinoma cells (Choi et al. 2015). Interestingly, in clear cell renal cell carcinoma MK-0457 inhibits the growth of tumors by targeting the proliferation of both tumor cells and tumor-associated endothelial cells (Li et al. 2010). Several clinical studies were initiated using MK-0457 in different human cancers. Phase I dose escalation study of this inhibitor was performed in adult patients with advanced solid tumors (Traynor et al. 2011). Most common dose-limiting toxicity was neutropenia and herpes zoster, and major adverse events were nausea, vomiting, diarrhea and fatigue. The maximum-tolerated dose was defined as 64 mg, and a total of 12 patients experienced stable disease, while one patient with advanced ovarian cancer achieved prolonged stable disease for 11 months. A phase I/II dose escalation study of MK-0457 was performed in patients with leukemias (Giles et al. 2013). Seventy-seven patients with refractory hematologic malignancies received 1–21 (in average 3) cycles of MK-0457, and maximum-tolerated doses were calculated for a 5-day short infusion as 40 mg and continuous infusion as 144 mg. Most common drug-related adverse events were transient mucositis and alopecia. 44 % (8/18) patients with BCR-ABL T315I-mutated chronic myelogenous leukemia had hematologic responses, and 33 % (1/3) patients with Philadelphia chromosome-positive acute lymphoblastic leukemia obtained complete remission. Another multicenter, nonrandomized, phase II study evaluated the safety and efficacy of MK-0457 and confirmed BCR-ABL T315I mutation was performed in patients with either CML or Ph+ ALL (Seymour et al. 2014). Fifty-two were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40, 32 or 24 mg. The most common
adverse events were neutropenia and febrile neutropenia. Totally, 8 % (4/52) of patients achieved major cytogenetic response and 6 % (3/52) achieved unconfirmed complete or partial response. 13 % (2/15) patients with chronic phase CML achieved complete hematologic response. No patients with advanced CML or Ph+ ALL achieved major hematologic response. VE-465 is a small-molecule inhibitor of Aurora kinases with IC50 of 1 nM for AURKA, 26 nM for AURKB and 8.7 nM for AURKC, which is structure analog of MK-0457 (Fig. 3). VE-465 also induces apoptosis in myeloma cell lines and primary myeloma plasma cells. The combination of VE-465 and dexamethasone improves cell killing compared with the use of either agent alone, even in cells resistant to the single agents. Similarly, another study showed antiproliferative activity and no antagonism with dexamethasone, doxorubicin, and bortezomib (Negri et al. 2009). In addition, it has been shown that VE-465 has strong anticancer effect in Huh-7 and HepG2 hepatocellular carcinoma cell lines as well as in Huh-7 nude mice xenograft model (Lin et al. 2009). It was also found that a combination of VE-465 and vincristine had a synergistic suppression influence on the growth of AML (HL60, U937, THP-1 and KY821), CML (KCL22, K562 and KU812) and primary leukemia cells (Yoshida et al. 2011). VE-465 and carboplatin also had a synergistic effect on cell viability and increase in apoptosis in ovarian cancers, which are either sensitive or resistant to platinum (Fu et al. 2012). GBM 8401, GBM 8901 and U87-MG glioblastoma multiforme cells treated with VE-465 had inhibited cell growth and increased polyploidy (Lee et al. 2013). PHA-680632 is potent inhibitor of Aurora kinases with IC50 of 27 nM for AURKA, 135 nM for AURKB and 120 nM for AURKC (Fig. 3). PHA-680632 had an antiproliferative effect in a panel of 35 cell lines of a different human cancer types, IC50 ranging between 0.29 and 1.56 μM (Soncini et al. 2006). The inhibitor treatmentinduced phenotypes are quite comparable to AURKA or AURKB RNAi. PHA-680632 also suppresses tumor growth in HL60 AML, A2780 ovarian carcinoma and HCT116 colon carcinoma cell xenograft models as well as syngeneic breast cancer model. Combined ionizing radiation and PHA680632 led enhancement of apoptosis and micronuclei formation in TP53-deficient HCT116 colorectal cancer cells (Tao et al. 2007). TP53-deficient HCT116 mice revealed higher tumor growth delay after the PHA680632 and ionizing radiation combined treatment compared with ionizing radiation alone. VE-465 was also effective in leukemia cells expressing T315I mutant form of BCR-ABL, which demonstrate decreased sensitivity to imatinib, as well as nude mice bearing same cells (Akahane et al. 2008).
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Selective inhibitors Hesperadin is ATP-competitive inhibitor of AURKB with IC50 of 250 nM (Fig. 4). It works via inhibitor of microtubule attachment to kinetochores, which is regulated by AURKB and has similar phenotype as AURK RNAi (Hauf et al. 2003). It has been shown to cause significant reduction in MCF7 breast and PC3 prostate cancer cell proliferation via presence of multiple mitotic defects caused by AURKB inhibition (Ladygina et al. 2005). Interesting findings were also observed in pathogenic Trypanosoma brucei in which hesperidin inhibits Aurora kinase-1 (TbAUK1) and blocks nuclear division and cytokinesis in bloodstream forms (Jetton et al. 2009). AZD1152-HQPA (barasertib) is a potent selective AURKB inhibitor with IC50 of 0.37 nM, which is 50-fold selective over AURKC and over 1000-fold over AURKA (Mortlock et al. 2007) (Fig. 4). It was shown that AZD1152 inhibited the proliferation of HL-60, NB4 and MOLM13 AML cell lines, PALL-2 ALL cell line, MV4-11 biphenotypic leukemia cell line, EOL-1 acute eosinophilic leukemia
Fig. 4 AZD1152, hesperadin and GSK1070916
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cell line and K562 blast crisis of CML cell line (Yang et al. 2007). AZD1152 effectively repressed progress of human colon, lung, and hematologic tumor xenografts in immunodeficient mice by inducing apoptosis and histone H3 phosphorylation (Wilkinson et al. 2007). It also induced growth arrest, apoptosis and the accumulation of hyperploid cells in AML cell lines and primary AML cultures (Walsby et al. 2008) as well as THP-1 cells both in vitro and in xenotransplants (Oke et al. 2009). AZD1152 also showed increased anti-multiple myeloma activity in purified patient plasma cell samples as well as murine xenograft tumor models (PMID: Evans et al. 2008). The inhibitor also boosted radiation treatment in p53-deficient HCT116 and A549 cells both in vitro as well as in xenotansplant (Tao et al. 2008). Androgen-resistant prostate cancer PC3 and DU-145 cells were also enhanced to radiosensitivity by the treating by AZD1152 (Niermann et al. 2011). Similar result was observed also in androgen-dependent prostate cancer cell line LNCaP (Zekri et al. 2015). Twelve human HCC cell lines were analyzed for the in vitro effects of AZD1152, and it was shown that inhibitor suppressed histone H3
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phosphorylation and induced apoptosis in a dose-dependent manner. Additionally, growth of subcutaneous xenografts was inhibited and tumor growth was slowed and survival increased in an orthotopic hepatoma model (PMID: Aihara et al. 2010). As in case with hesperidin, it seems that mutant FLT3 is a secondary target of AZD1152, and FLT3-ITD primary samples are predominantly sensitive to this inhibitor (Grundy et al. 2010). AZD1152 also had anti-tumor effects on Burkitt’s and Hodgkin’s lymphoma in human tissues, cell cultures and murine xenograft (Mori et al. 2011). Human ovarian cancer cell line SKOV3 had an enhancement of AZD1152 on the effect of platinum to which otherwise this cell line is resistant (Ma et al. 2013). The success of preclinical research on AZD1152 induces quite a number of clinical studies of this inhibitor. Phase I study for the evaluation of the safety and efficacy as well as pharmacokinetics in advanced AML was performed in Japanese patients (Tsuboi et al. 2011). 50–1200 mg of AZD1152 was administered as a constant 7-day intravenous injection every 21 days. No dose-limiting toxicities were reported, and neutropenia was the most usually reported adverse occurrence; the response rate of 19 % was achieved. Similar phase I/II study in advanced AML was performed in Netherlands (Löwenberg et al. 2011). In part A, 32 patients were treated with AZD1152 (50–1600 mg). Dose-limiting toxicities were reported in the 800–1600 mg groups, and the maximum-tolerated dose was defined as 1200 mg for the part B (also 32 patients). In both parts, the most usually reported adverse events were febrile neutropenia (24 patients) and stomatitis/mucosal inflammation (16 patients). The response rate was 25 % for study parts A and B combined (64 patients) and 26 % for patients who received the 1200 mg of AZD1152 in both parts combined (38 patients). Another phase I study on solid tumors was also performed in Netherlands (Boss et al. 2011). Multicentre dose-escalation study was performed in which AZD1152 was administered as a 2-h intravenous injection given every 7 days (part A) in 19 patients or 14 days (part B) in 40 patients. Adverse events neutropenia and leukopenia occurred in 58 and 11 % of patients in part A and 43 and 20 % in part B. No tumor responses were observed at any dose, though stable disease was achieved in 25 % patients total. Yet another phase I study in solid tumors, performed in Netherlands, used four different dosing treatments with AZD1152 in total of 79 patients (Keizer et al. 2012). Using plasma concentrations and neutrophil count data from first study, a pharmacokinetic and pharmacodynamic model was developed and later used to predict the safe initial dose for the later trials. Expected safe initial dose levels were higher than those used in two following trials, but lower than used in the other trial. Phase I study using AML patients was also performed in UK (Dennis et al. 2012). Five patients with newly diagnosed, relapsed
or refractory AML received 1200 mg of AZD1152 as a 7-day continuous injection every 28 days. The most common adverse events observed were nausea and stomatitis, and one of the four patients evaluable for response entered complete remission. Phase I study assessing the safety and tolerability of AZD1152 combined low-dose cytosine arabinoside in patients 60 years or older was performed in USA (Kantarjian et al. 2013). Twenty-two patients received treatment cycle 800–1200 mg of AZD1152. Dose-limiting toxicities were reported in two patients (stomatitis/mucositis; 1200 mg cohort). The most common adverse events were infection (73 %), febrile neutropenia (59 %), nausea (50 %) and diarrhea (46 %). AZD1152 plus low-dose cytosine arabinoside resulted in an overall response rate of 45 % (10/22 patients). Another phase I study in patients with advanced solid tumors was also performed in USA (Schwartz et al. 2013). Thirty-five patients with advanced solid malignancies were treated with escalating doses of AZD1152, injected either as 48-h continuous infusion or as two 2-h infusions on consecutive days, both every 14 days of a 28-day cycle. Adverse event was neutropenia, which occurred in 34 % of patients in total and no tumor responses were observed, though stable disease was observed in 23 % of patients. A phase II study was performed in 15 B cell lymphoma patients in UK (Collins et al. 2015). Patients received up to six cycles of 800 mg AZD1152 as a continuous 96-h intravenous injection, starting on day 1 of the 21-day cycle. No serious adverse reactions or fatal serious adverse events occurred. Other toxicities were brief, controllable and predictable, such as neutropenia occurred in 47 %, nausea in 60 %, diarrhea in 53 %, anemia in 33 %, fatigue in 33 % and mucositis 13 % patients. Eight patients had reduction in tumor size (5–81 %). GSK1070916 is a reversible and ATP-competitive inhibitor of AURKB and AURKC with IC50 of 3.5 nM for AURKB and 6.5 nM for AURKC (Fig. 4). It is more than 250-fold selective against the AURKA. In vitro treatment of A549 human lung cancer cells with GSK1070916 has an effective antiproliferative outcome (Adams et al. 2010; Anderson et al. 2009). The effect of GSK1070916 on cancer cell proliferation was also tested by treating 161 different cancer cell lines (Hardwicke et al. 2009). Effective effects on cell proliferation in various cancer types were detected, showing more than 100 cell lines effected by EC50 lover than 10 nmol/L. It also created antitumor activity in a number of xenografts in nude mice namely A549 lung cancer, HCT116 colon cancer, HL60 AML and K562 CML, as well as less pronounced effect in Colo205 and SW620 colon cancer, H460 lung cancer and MCF-7 breast cancer. GSK1070916 was assessed for antitumor activity in two human AML SCID mouse models (HL60 and MV-4-11) and a dose-dependent increase in the median survival times was detected in both models. On the other
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Fig. 5 MLN8054, MLN8237 and PF-03814735
side, the analysis of 59 hematological cancer-derived cell lines showed only 20 cell lines sensitive and 39 resistant to GSK1070916 treatment (Moy et al. 2011). High chromosome number and polyploidy was more predominant in the cell lines, which were resistant to the treatment. MLN8054 is a potent and selective inhibitor of AURKA with IC50 of 4 nM, which is more than 40-fold selective for AURKA than AURKB (Manfredi et al. 2007) (Figs. 1, 5). The growth of nine cancer cell lines (colon, breast, prostate, lung and ovary) was effectively inhibited by the treating with MLN8054 and HCT-116 colorectal and PC3 prostate tumor xenografts were affected in same manner as cell lines. Treatment with this inhibitor also leads to the p73-dependent apoptosis of H1299, TE7 and HCT116p53(−/−) p53-deficient cells (Dar et al. 2008). Interestingly, MLN8054 causes senescence in HCT-116 cancer cell xenografts in addition to growth inhibition (Huck et al. 2010). MLN8054 also sensitized PC3 and DU-145 androgen-resistant prostate cancer to radiation therapy in vivo or PC3 tumor cells in nude mice (Moretti et al. 2011). Quite successive preclinical studies with MLN8054 initiated a few clinical studies using this inhibitor. Phase I study of MLN8054 was performed in patients with
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advanced solid tumors with a major focus on safety, pharmacokinetics, and pharmacodynamics (Macarulla et al. 2010). Totally nine different groups of patients (43 in total) were given either single daily doses 4-times-daily dosing for 14 consecutive days of MLN8054 (10–20 mg) for 2 weeks (days 1–5 and 8–12) or 4-times-daily dosing for 14 consecutive days of divided doses (25–80 mg). Transaminitis, somnolence and hepatotoxicity were most commonly reported dose-limiting toxicities in several patients, usually in groups of higher doses. Pharmacodynamic analyses of skin and tumor mitotic indices, mitotic cell chromosome alignment and spindle bipolarity showed clear AURKA inhibition. However, complete or partial responses were seen in any patient, and only one patient with non-small cell lung cancer had stable disease for four cycles of MLN8054 treatment. Another phase I study in which MLN8054 given orally for 7, 14, or 21 days to 61 patients with advanced solid tumors showed stable disease in three patients (Dees et al. 2012). Most common adverse events were somnolence, fatigue, confusion, nausea and vomiting, and no complete or partial responses were seen, thus recommended dose for investigation in Phase 2 trials was not established. Millennium Pharmaceuticals initiated phase I
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study, assessed not only medical effect, but also biological influences, such as AURKA modulation, chromosome alignment and spindle bipolarity (Chakravarty et al. 2011). MLN8237 (alisertib) is a selective AURKA inhibitor with IC50 of 1.2 nM, which is more than 200-fold more selective for AURKA than AURKB (Manfredi et al. 2011) (Fig. 5). This inhibitor was used in Pediatric Preclinical Testing Program organized study, which assessed the activity of MLN8237 in a panel of cancer cells, such as rhabdomyosarcoma, Ewing sarcoma, glioblastoma, neuroblastoma, ALL, AML, anaplastic large-cell lymphoma (ALCL) and non-Hodgkin lymphoma (Maris et al. 2010). IC50 for most of the cell lines was 18–230 nM (except Rh18 rhabdomyosarcoma line). Good results were also seen using xenograft models: 11 out of 38 evaluable lines showed high activity of inhibitor with final tumor sizes less than the primary and additional 15 models showed intermediate activity. The antitumor effect of MLN8237 was also assessed in multiple myeloma cells, as well as IL6dependent INA-6 plasma cell leukemia cell lines which showed effects in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence (Görgün et al. 2010). Significant overall survival and reduced tumor burden in xenograft model of multiple myeloma were seen in mice treated with 30 mg/kg MLN8237 for 21 days. Treatment with MLN8237 also inhibited the growth and survival of K562 and LAMA 84 CML cell lines with IC50 57–87 nM (Kelly et al. 2011). Interestingly, this inhibitor kept activity against the T315I and E255 K BCR-ABL mutations, which have the highest resistance to imatinib therapy. In addition, combination of MLN8237 and nilotinib resulted in better apoptosis and growth inhibition than by any of drug alone. This cooperation also helped to decrease tumor load in K562 cell xenografts. In yet another study, MLN8237 inhibited aggressive B cell non-Hodgkin lymphoma viability and induced apoptosis, which was enhanced by the combination with docetaxel (Qi et al. 2011). The inhibitor plus docetaxel also inhibited tumor growth and increased survival in a mantle cell lymphoma xenograft mouse model. The combination of MLN8237 and cisplatin induced cell death in esophageal adenocarcinoma cells as well as had anti-tumor activity in vivo and in xenograft models (Sehdev et al. 2012). Combination with vorinostat showed additive cytotoxicity in pediatric leukemia, medulloblastoma and neuroblastoma cell lines (Muscal et al. 2013). MLN8237 also induced cell cycle arrest, aneuploidy and apoptosis in the bladder cancer cell lines T24 and UM-UC-3 and nude mouse bladder cancer xenograft model (Zhou et al. 2013). Apoptosis was induced and proliferation reduced in human tongue squamous cell carcinoma cell lines as well as tumor size and weight decreased in xenografted tumors by the inhibitor (Qi and
Zhang 2015). Cell cycle arrest, apoptosis and autophagy were induced by MLN8237 in MCF7 and MDA-MB-231 breast cancer cell lines (Li et al. 2015) and U-2 OS and MG-63 osteosarcoma cell lines (Niu et al. 2015). After a number of successful preclinical studies using MLN8237, several clinical trials were initiated. Phase I pharmacokinetic/pharmacodynamic study of MLN8237 was performed in patients with advanced solid tumors (Cervantes et al. 2012). Patients received MLN8237 once daily or twice daily for 7, 14, or 21 successive days, followed by 14 days recovery, in cycles of 21, 28 or 35. Main doselimiting toxicities were neutropenia and stomatitis, and the maximum-tolerated dose was 50 mg once or twice a day. Mitotic cells with characteristic spindle and chromosomal abnormalities in tumor samples were the major hallmark of AURKA inhibition by MLN8237. Similar phase I study, performed in Lineberger Comprehensive Cancer Center, showed very similar results: major toxicities were fatigue, nausea and neutropenia, maximum-tolerated dose of 50 mg twice daily and mitotic index was major indication of AURKA inhibition (Dees et al. 2011). Phase I trial was also performed in 37 child patients with refractory/recurrent solid tumors (Mossé et al. 2012). Children tolerated a higher dose of 80 mg; however, mucositis and myelosuppression were dose limiting on the twice-daily schedule, thus once daily for 7 days regiment was suggested. Phase I studies in adult cancer patients also valued pharmacokinetics, pharmacodynamics, and exposure-safety to support phase II/III dosing selection and found that 7-day schedule of 50 mg twice a day is estimated to result AURKA inhibition in tumors (Venkatakrishnan et al. 2014). Fifty-eight patients of multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia were also enrolled in phase I study (Kelly et al. 2014). The most frequent drug-related toxicities were neutropenia, thrombocytopenia, anemia and leukopenia and the maximum-tolerated dose was 50 mg twice day on 7-day schedule. Oral application of MLN8237 as enteric-coated tablet was tested in 24 patients’ nonhematologic malignancies in phase I study (Falchook et al. 2014). The most common drug-related adverse event was neutropenia, and again 7-day schedule of 50 mg twice a day was found the most suited for further studies. The phase II study in 57 patients with AML or high-grade myelodysplastic syndrome which received MLN8237 50 mg twice a day for 7 days in 21-day cycles was performed (Goldberg et al. 2014). Major adverse events were diarrhea, fatigue, nausea, febrile neutropenia and stomatitis and 17 % (6/35) response rate and 49 % (17/35) stable disease was achieved in AML patients. Another phase II study, using same regiment of MLN8237, was performed in 37 T cell lymphoma patients (Barr et al. 2015). Major adverse events in several patients were neutropenia, anemia, thrombocytopenia, febrile neutropenia, mucositis and rash. Overall response
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Fig. 6 ZM 447439, MK-5108 and TC-A 2317
rate was 30 %, which led to international randomized phase III trial on MLN8237 in T-cell lymphoma. PF-03814735 is ATP-competitive inhibitor of AURKA and AURKB with IC50 0.8 nM for AURKA and 5 nM for AURKB (Jani et al. 2010) (Fig. 5). Additional 19 kinases were also inhibited by this inhibitor, however at higher concentrations as A and B Aurora kinases. PF-03814735 at IC50 42–150 nmol/L was also showed to inhibit cell proliferation of several human cancer cells (HCT-116, HL-60, A549, and H125) as well as cancer cells of rat (C6), mouse (L1210) and dog (MDCK). In addition, substantial antitumor effectiveness of 20 mg/kg inhibitor was observed in six xenograft tumor models, including A2780 ovarian cancer, MDA-MB-231 breast cancer, HCT-116, colo-205 and SW620 colorectal cancer, and HL-60 acute promyelocytic leukemia. Mice bearing SW620 or A2780 xenografts showed approximately 60 % tumor growth inhibition after being treated orally with 20 mg/kg PF-03814735 once daily for 10 days and intervenally with 20 mg/kg docetaxel on study days 1 and 8. Phase I study in patients with advanced solid tumors was initiated in order to evaluate the safe dose, pharmacokinetics and pharmacodynamics of PF-03814735 (Schöffski et al. 2011). Fifty-seven patients received once daily, oral PF-03814735 on plan A (days 1–5; 5–100 mg) or plan B (days 1–10; 40–60 mg) of 21-day cycles. Most
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common dose-limiting toxicities were febrile neutropenia, increased levels of aspartate amino transferase, left ventricular dysfunction and prolonged low-grade neutropenia. Adverse events were primarily mild to moderate and included diarrhea, fatigue, nausea and vomiting and 19 patients achieved stable disease. In small cell lung cancer cell lines the status of the Myc gene family and retinoblastoma pathway members significantly correlated with the efficacy of PF-03814735 (Hook et al. 2012). Experiments with two small cell lung cancer xenografts confirmed the sensitivity schedule dependence of Myc gene-driven xenografts to PF-03814735. MK-5108 (VX-689) is a highly selective AURKA inhibitor with IC50 of 0.064 nM, which is 220-fold more selective than for AURKB and 190-fold for AURKC (Shimomura et al. 2010) (Fig. 6). Seventeen human breast, cervix, colon, ovary and pancreas cancer cell lines showed antitumor activity treated with 0.16–6.4 μmol/L MK-5108. In HCT116 SCID mice bearing HCT-116 xenografts, treated with 15–30 mg/kg inhibitor as well as nude rats bearing SW48 xenografts treated with 15–45 mg/kg tumor growth inhibition was observed as well. Additionally, the combination of MK-5108 and docetaxel showed higher antitumor activities compared with animals treated with only docetaxel or control animals. Non-small cell lung cancer cell lines are also
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sensitive to anti-proliferative activity of MK-5108 alone and in combination with cisplatin or docetaxel (Chinn et al. 2014). Successful preclinical results with MK-5108 lead to the phase I study of this inhibitor as monotherapy as well as in combination with docetaxel, in patients with solid tumors (Amin et al. 2015). No dose-limiting toxicities were observed in Panel 1 (18 patients, 200–1800 mg) and three patients in Panel 2 (17 patients; 100–225 mg with combination of 60 mg docetaxel) had febrile neutropenia or infection. Best results were stabile disease in half of patients. TC-A 2317 hydrochloride Potent AURKA inhibitor with IC50 of 1.2 nM is 100-fold more selective than for AURKB (101 nM) (Ando et al. 2010) (Fig. 6). This inhibitor-repressed growth and survival of B9, GB30 and GB169 neurosphere cells were derived from intracranial glioblastoma patient surgical samples at a concentration 168–179 nM (Van Brocklyn et al. 2014). It also induces cell apoptosis and senescence in those neurospheres. Not much more of the preclinical and no clinical studies are performed with TC-A 2317 so far. ZM 447439 is a selective and ATP-competitive inhibitor with IC50 of 50 nM for AURKB, which is more selective than other Aurora kinases (1000 nM for AURKA, 250 nM for AURKC) and approximately 200-fold more selective than other kinases, such as CDKs or PLK1 (Fig. 6). The treatment of the different anaplastic thyroid cancer cells with IC50 0.5–5 mM ZM447439 inhibited proliferation. Additionally, the inhibitor extraordinarily diminished the formation of colonies in soft agar of those cell lines. In three different gastroenteropancreatic neuroendocrine tumor cell lines (BON, QGP-1 and MIP-101), proliferation was inhibited apoptosis induced and cell cycle blocked (Georgieva et al. 2010). Additionally, combined treatment with the chemotherapeutic agents streptozocin and cisplatin increased significantly the antiproliferative effects of those agents. The growth of cervical cancer cell line SiHa was inhibited by ZM447439, cisplatin and the combination of both, which had higher efficiency that single treatments (Zhang and Zhang 2011). Combined treatment also increased S-phase arrest and apoptosis in these cells. ZM447439 also decreased the proliferation and initiated radiosensitization both alone as well as synergistically with temozolomide in primary cultures or cell lines of glioblastoma (Borges et al. 2012). The inhibitor was also capable for inhibition of proliferation and colony formation in a primary childhood adrenocortical tumor culture with TP53 p.R337H mutation (Borges et al. 2013).
Perspectives Latest advances in the small-molecule inhibitors of Aurora kinases arena steered quite a figure of compounds with a
diverse choice of the inhibited molecules, antitumor potencies as well as ways of biological accomplishments. However, there still is plentiful room for development. For example, it is still unclear which AURK or collection of AURKs ought to be targeted in a medical situation. So far, both preclinical and clinical studies show some pan-AURK as well as some selective ones as good candidates for targeted therapy. It is still to be determined whether it is better to use highly selective or rather broad range inhibitors, or the decision could depend on the type of cancer and the molecules involved. Aurora kinase inhibitors under clinical trials are ATPcompetitive inhibitors (Fig. 1) as opposed to some other kinase inhibitors which are allosteric non-ATP-competitive inhibitors. MEK kinase CI-1040 is the most well-known allosteric inhibitor to date. Non-ATP-competitive inhibitors usually have greater kinase selectivity and they can perform better in the presence of ATP; therefore, they are in demand in the pharmaceutical industry. On the other hand, it seems that in some cases the combination therapies using AURK inhibitors and some chemotherapeutic agents are as effective as or even more promising than the use of these inhibitors as single agents. Therefore, more drugs have to be assessed in combination with AURK inhibitors. In addition, based on the successful studies in other kinases, it could be suggested that the combinations between different kinase inhibitors could be a very good solution. Therefore, this field of clinical research should also be used in case of aurora kinases and their inhibitors. Partially, this field is already pursued in the use of multikinase inhibitors, which also inhibit AURKs, among other kinases, such as: KW-2449, CYC116, ENMD2076, R763, XL228, PHA739358, JNJ-7706621, SU-6668 and AT-9283. Compliance with ethical standards Conflict of interest Author declares that he has no conflict of interest. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.
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