A novel class of pyrazole analogues as aurora kinase A inhibitor: design, synthesis, and anticancer evaluation.

Pyrazole, as a small molecule, was discovered for higher cytotoxicity and affinity towards Aurora-A kinase. Based on these facts, a novel pyrazole substituted at the 4th position was designed, synthesized, and evaluated against MCF-7, MDA-MB-23, and Vero (non-cancerous kidney cell) cell lines. Compounds5hand5eexhibited greater cytotoxicity in the series against MCF-7 and MDA-MB-231, with GI50 values of 0.12 µM and 0.63 µM, respectively, as compared to Imatinib (GI50 values of 16.08 µM and 10.36 µM). All of the compounds displayed selective cytotoxicity against cancer cells but not on normal Vero cells, supporting the design strategy to be a selective anticancer agent. Furthermore, compounds 5h and 5e inhibited Aurora-A kinase with IC50 values of 0.78 µM (4.70-fold) and 1.12 µM (2.84-fold), respectively, as compared to alisertib (IC50 = 3.36 µM). In addition, compound 5h significantly arrested the cell cycle at G2/M (34.89 %, 5.56-fold) and the apoptotic phase (25.04 %, 11.81-fold) compared to the control. It also triggered an increase in early (7.43 %) and late (14.89 %) phase apoptosis compared to vehicle (0.235 and 0.36 %, respectively), causing 37.89-fold higher total apoptosis in the annexin-V assay. These data imply that Aurora-A kinase inhibition may be linked to apoptosis induction and cell cycle arrest. Furthermore, their higher docking score in the study confirmed evidence of Aurora-kinase suppression. It was observed that fluorine and imidazole increased the H-bond and lipophilic interactions with the binding residue. Also, the substitution of electron-rich and lipophilic groups increased hydrophobic interactions. Moreover, the three-atom linkage (CH2NHCH2) expanded compound 5h to fill the cavity. Based on current findings, it is concluded that compounds 5h and 5e with strong Aurora-A kinase suppression may be promising anticancer agents.

Aurora kinase A inhibitor, LY3295668 erbumine: a phase 1 monotherapy safety study in patients with locally advanced or metastatic solid tumors.

Background Aurora A kinase (AurA) overexpression likely contributes to tumorigenesis and therefore represents an attractive target for cancer therapeutics. This phase 1 study aimed to determine the safety, pharmacokinetics, and antitumor activity of LY3295668 erbumine, an AurA inhibitor, in patients with locally advanced or metastatic solid tumors. Methods Patients with locally advanced or metastatic solid tumors, Eastern Cooperative Oncology Group performance status 0-1, and disease progression after one to four prior treatment regimens were enrolled. Primary objective was to determine maximum tolerated dose (MTD); secondary objectives included evaluation of the tolerability and safety profile and pharmacokinetics of LY3295668. All patients received twice-daily (BID) oral LY3295668 in 21-day cycles in an ascending-dose schedule. Results Twelve patients were enrolled in phase 1 (25 mg, n = 8; 50 mg, n = 2; 75 mg, n = 2) and one patient was enrolled after. Overall, four patients experienced dose-limiting toxicities (DLTs) within the first cycle (75 mg: Grade 3 diarrhea [one patient], Grade 4 mucositis and Grade 3 corneal deposits [one patient]; 50 mg: mucositis and diarrhea [both Grade 3, one patient]; 25 mg: Grade 3 mucositis [one patient]). Patients exhibiting DLTs had the highest model-predicted exposures at steady state. Mucositis was the most common adverse event (67%), followed by diarrhea, fatigue, alopecia, anorexia, constipation, and nausea. Nine patients had best response of stable disease; the disease control rate was 69%. Conclusions MTD of LY3295668 was 25 mg BID. LY3295668 had a manageable toxicity profile and demonstrated activity in some patients with locally advanced or metastatic solid tumors.Trial registration ClinicalTrials.gov, NCT03092934. Registered March 22, 2017. https://clinicaltrials.gov/ct2/show/NCT03092934 .

Global population pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in cancer patients: rationale for lower dosage in Asia.

AIMS: This population pharmacokinetic analysis was conducted to describe quantitatively the regional differences and sources of interpatient variability on the apparent oral clearance of alisertib. METHODS: A population pharmacokinetic analysis was performed on data from 671 cancer patients in Western countries and in Japan/East Asia to whom alisertib 5-150 mg once or twice daily (b.i.d.) was administered in multiple dosing schedules. The final model was used to simulate alisertib pharmacokinetics in patients in the West and East Asian regions in the single-agent schedule of 7 days of dosing in a 21-day cycle. Exposure-safety relationships for mechanism-related antiproliferative toxicities (neutropenia, mucositis and diarrhoea) were estimated by logistic regression. RESULTS: Alisertib pharmacokinetics were described by a two-compartment model with four-transit compartment absorption and linear elimination. The final model included a covariate effect of region on relative bioavailability, with patients in the East Asian region estimated to have a 52% higher bioavailability compared with Western patients. Population simulated exposure at 30 mg b.i.d. in patients in Asia was similar to that at 50 mg b.i.d. in Western patients [geometric mean (coefficient of variation) steady state area under the concentration-time curve over the dosing interval (AUC(0-τ) ): 21.4 µM.h (52.3%) and 24.1 µM.h (53.6%), respectively]. Exposure-AE relationships could be described for neutropenia, stomatitis and diarrhoea, supporting the lower dosage of alisertib in Asia for global clinical development. CONCLUSIONS: Model-based simulations support the achievement of similar alisertib exposures in patients in Asia who are administered a 40% lower dose compared with the Western population, thereby providing a quantitative clinical pharmacology bridging and regional dosing rationale for global drug development.

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors.

BACKGROUND: MK-5108 is a potent/highly selective Aurora A kinase inhibitor. METHODS: A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m(2), determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. RESULTS: 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). CONCLUSIONS: MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 µM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.

The role of alisertib in treatment of peripheral T-cell lymphomas.

Peripheral T-cell lymphomas are aggressive lymphomas with poor outcomes for which novel treatments are urgently needed. Alisertib (MLN8237) is a second-generation oral Aurora A kinase inhibitor. Treatment with alisertib results in an accumulation of cells with abnormal mitotic spindles, leading to decreased proliferation and apoptosis in a range of human tumor cell lines. Alisertib has shown single-agent antitumor activity in animal xenograft models and promising antitumor activity alone or in combination with other agents in patients with solid and hematologic cancers, and T-cell lymphomas in particular. It is currently being tested in randomized controlled Phase III trials in relapsed/refractory peripheral T-cell lymphoma.

Sensitisation of Cancer Cells to MLN8237, an Aurora-A Inhibitor, by YAP/TAZ Inactivation.

BACKGROUND: Transcriptional co-activators YES-associated protein (YAP) and transcriptional coactivator with PDZ-motif (TAZ) stimulate the expression of cell cycle-related genes to permit for tumour cell growth. MLN8237 is a potent aurora-A kinase inhibitor; however, patients responding to MLN8237 are limited. Therefore, rational combination therapy could enhance their response. MATERIALS AND METHODS: YAP and TAZ were depleted using siRNA and then treated with MLN8237 in YAP/TAZ-dependent OVCAR-8 and MDA-MB-231 cell lines. MLN8237 was combined with fluvastatin, an agent constraining nuclear localisation of YAP/TAZ for potential combination therapy in vitro. RESULTS: Depletion of either YAP or TAZ sensitised these cell lines to MLN8237, resulting in apoptosis and reduction in aurora-A. MLN8237 reduced YAP/TAZ expression. A combination of MLN8237 with fluvastatin effectively reduced the cell viability of OVCAR-8 and MDA-MB-231 cell lines. CONCLUSION: A combination of MLN8237 and small-molecule agents inactivating YAP/TAZ, such as statins, could be a novel therapeutic strategy for YAP/TAZ-dependent cancer.

Co-delivery of Aurora-A inhibitor XY-4 and Bcl-xl siRNA enhances antitumor efficacy for melanoma therapy.

BACKGROUND: The newly synthesized Aurora-A kinase inhibitor XY-4 is a potential anti-cancer agent, but its hydrophobicity and limited efficiency restrict further application. Nanotechnology based combined therapy provides an optimized strategy for solving these issues. METHODS: In this study, the newly synthesized Aurora-A kinase inhibitor XY-4 and Bcl-xl targeted siRNA were co-delivered by cationic liposomes, creating an injectable co-delivery formulation. The anti-cancer ability and mechanisms of XY-4/Bcl-xl siRNA co-loaded cationic liposomes were studied both in vitro and in vivo. RESULTS: The prepared liposomes had a mean particle size of 91.3±4.5 nm with a zeta potential of 38.5±0.5 mV and were monodispersed (Polydispersity index =0.183) in water solution, with high drug loading capacity and stability. Intriguingly, the positive charges of co-delivery liposomes not only facilitated gene delivery, but also obviously enhanced drug uptake. The XY-4/Bcl-xl siRNA co-loaded cationic liposomes demonstrated enhanced anti-cancer effects on B16 melanoma cells in vitro by activation mitochondrial apoptosis pathway. Moreover, intratumoral injection of this co-delivery formulation efficiently inhibited the growth of a B16 melanoma xenograft model in vivo. CONCLUSION: By co-delivering Aurora-A kinase inhibitor XY-4 and Bcl-xl targeting siRNA in a nanoformulation, our study supplied a potential combination strategy for melanoma therapy.

Aurora A Functional Single Nucleotide Polymorphism (SNP) Correlates With Clinical Outcome in Patients With Advanced Solid Tumors Treated With Alisertib, an Investigational Aurora A Kinase Inhibitor.

BACKGROUND: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. METHODS: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n=62) or paclitaxel alone (n=60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. FINDINGS: TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p<0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n=53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n=32, 38%; HR 0.5; p=0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n=47, 39%) had a trend towards improved PFS (7.5months) vs paclitaxel alone (n=32, 26%; 3.8months; HR 0.618; p=0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set. INTERPRETATION: These findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted.

Recent advances in the development of Aurora kinases inhibitors in hematological malignancies.

Over the last two decades, since the discovery of Drosophila mutants in 1995, much effort has been made to understand Aurora kinase biology. Three mammalian subtypes have been identified thus far which include the Aurora A, B and C kinases. These regulatory proteins specifically work at the cytoskeleton and chromosomal structures between the kinetochores and have vital functions in the early phases of the mitotic cell cycle. Today, there are multiple phase I and phase II clinical trials as well as numerous preclinical studies taking place looking at Aurora kinase inhibitors in both hematologic and solid malignancies. This review focuses on the preclinical and clinical development of Aurora kinase inhibitors in hematological malignancy and discusses their therapeutic potential.

An exploratory phase 2 study of investigational Aurora A kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes.

Alisertib (MLN8237) is an investigational, oral, selective, Aurora A kinase (AAK) inhibitor. In this phase 2 trial, 57 patients with acute myeloid leukemia (AML) or high-grade myelodysplastic syndrome received alisertib 50 mg BID for 7 days in 21-day cycles. Responses in 6/35 AML patients (17% response rate with an additional 49% stable disease, 34% transfusion independence) included 1 complete response lasting >1 year. No responses were observed in MDS patients. Adverse events >30% included diarrhea, fatigue, nausea, febrile neutropenia, and stomatitis. Results suggest modest activity in AML, supporting further research to better understand how AAK inhibition may induce leukemic cell senescence.