MLN8237

• CAT Number: I000178
• CAS Number: 1028486-01-2
• Molecular Formula: C₂₇H₂₀ClFN₄O₄
• Molecular Weight: 518.9
• Purity: ≥95%
• Synonyms: 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid
• Target: Aurora Kinase
• Solubility: DMSO: ≥ 28 mg/mL
• Storage: 3 years -20C powder
• IC50: 1.2 nM (Aurora A)
• InChI: InChI=1S/C27H20ClFN4O4/c1-36-21-5-3-4-20(29)23(21)25-19-10-15(28)6-8-17(19)24-14(12-30-25)13-31-27(33-24)32-16-7-9-18(26(34)35)22(11-16)37-2/h3-11,13H,12H2,1-2H3,(H,34,35)(H,31,32,33)
• InChIKey: ZLHFILGSQDJULK-UHFFFAOYSA-N
• SMILES: COC1=C(C(=CC=C1)F)C2=NCC3=CN=C(N=C3C4=C2C=C(C=C4)Cl)NC5=CC(=C(C=C5)C(=O)O)OC

Alisertib (MLN8237) is a selective Aurora A inhibitor with IC50 of 1.2 nM; has >200-fold higher selectivity for Aurora A than Aurora B.IC50 Value: 1.2 nM (Aurora A)Target: Aurora Ain vitro: MLN8237 (0.5 μM) treatment inhibits the phosphorylation of Aurora A in MM1.S and OPM1 cells, without affecting the Aurora B mediated histone H3 phosphorylation. MLN8237 significantly inhibits cell proliferation in multiple myeloma (MM) cell lines with IC50 values of 0.003-1.71 μM. MLN8237 displays more potent anti-proliferation activity against primary MM cells and MM cell lines in the presence of BM stroma cells, as well as IL-6 and IGF-1 than against MM cells alone. MLN8237 (0.5 μM) induces 2- to 6-fold increase in G2/M phase in primary MM cells and cell lines, as well as significant apoptosis and senescence, involving the up-regulation of p53, p21 and p27, as well as PARP, caspase 3, and caspase 9 cleavage. In addition, MLN8237 shows strong synergistic anti-MM effect with dexamethasone, as well as additive effect with doxorubicin and bortezomib. MLN8237 shows >200-fold higher selectivity for Aurora A than the structurally related Aurora B with an IC50 of 396.5 nM, and does not have any significant activity against 205 other kinases.in vivo: MLN8237 significantly reduces the tumor burden with tumor growth inhibition (TGI) of 42% and 80% at 15 mg/kg and 30 mg/kg, respectively, and prolongs the survival of mice compared with the control.

Reference

1:Cisplatin-resistant cancer cells are sensitive to Aurora kinase A inhibition by alisertib. Wang L, Arras J, Katsha A, Hamdan S, Belkhiri A, Ecsedy J, El-Rifai W.Mol Oncol. 2017 Apr 18. doi: 10.1002/1878-0261.12066. [Epub ahead of print] PMID: 28417568 Free Article2:Alisertib induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt/mTOR- and p38 MAPK-mediated pathways in human glioblastoma cells. Liu Z, Wang F, Zhou ZW, Xia HC, Wang XY, Yang YX, He ZX, Sun T, Zhou SF.Am J Transl Res. 2017 Mar 15;9(3):845-873. eCollection 2017. PMID: 28386317 Free PMC Article3:A phase 2 trial of alisertib in patients with relapsed or refractory B-cellnon-Hodgkin lymphoma. Cohen JB, Maddocks KJ, Huang Y, Christian BA, Jaglowski SM, Flowers CR, Blum KA.Leuk Lymphoma. 2017 Feb 20:1-2. doi: 10.1080/10428194.2017.1289527. [Epub ahead of print] No abstract available. PMID: 28278718 4:A Phase I/II Study of the Investigational Drug Alisertib in Combination With Abiraterone and Prednisone for Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Abiraterone. Lin J, Patel SA, Sama AR, Hoffman-Censits JH, Kennedy B, Kilpatrick D, Ye Z, Yang H, Mu Z, Leiby B, Lewis N, Cristofanilli M, Kelly WK.Oncologist. 2016 Nov;21(11):1296-1297e. doi: 10.1634/theoncologist.2016-0297. Epub 2016 Oct 24. PMID: 28178640 Free PMC Article5:Association of an aurora kinase a (AURKA) gene polymorphism with progression-free survival in patients with advanced urothelial carcinoma treated with the selective aurora kinase a inhibitor alisertib. Necchi A, Pintarelli G, Raggi D, Giannatempo P, Colombo F.Invest New Drugs. 2017 Feb 3. doi: 10.1007/s10637-017-0440-5. [Epub ahead of print] PMID: 28155045 6:A phase 2 study of alisertib (MLN8237) in recurrent or persistent uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group study 0231D. Hyman DM, Sill MW, Lankes HA, Piekarz R, Shahin MS, Ridgway MR, Backes F, Tenney ME, Mathews CA, Hoffman JS, Aghajanian C, Hensley ML.Gynecol Oncol. 2017 Jan;144(1):96-100. doi: 10.1016/j.ygyno.2016.10.036. Epub 2016 Oct 27. PMID: 28094040 7:Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia. Fathi AT, Wander SA, Blonquist TM, Brunner AM, Amrein PC, Supko J, Hermance NM, Manning AL, Sadrzadeh H, Ballen KK, Attar EC, Graubert TA, Hobbs G, Joseph C, Perry AM, Burke M, Silver R, Foster J, Bergeron M, Ramos AY, Som TT, Fishman KM, McGregor KL, Connolly C, Neuberg DS, Chen YB.Haematologica. 2017 Apr;102(4):719-727. doi: 10.3324/haematol.2016.158394. Epub 2016 Dec 29. PMID: 28034990 Free Article8:Alisertib demonstrates significant antitumor activity in bevacizumab resistant, patient derived orthotopic models of glioblastoma. Kurokawa C, Geekiyanage H, Allen C, Iankov I, Schroeder M, Carlson B, Bakken K, Sarkaria J, Ecsedy JA, D/’Assoro A, Friday B, Galanis E.J Neurooncol. 2017 Jan;131(1):41-48. doi: 10.1007/s11060-016-2285-8. Epub 2016 Nov 5. PMID: 27816996 9:Phase II study of MLN8237 (Alisertib) in advanced/metastatic sarcoma. Dickson MA, Mahoney MR, Tap WD, D/’Angelo SP, Keohan ML, Van Tine BA, Agulnik M, Horvath LE, Nair JS, Schwartz GK.Ann Oncol. 2016 Oct;27(10):1855-60. doi: 10.1093/annonc/mdw281. Epub 2016 Aug 8. PMID: 27502708 10:First Multicenter, Randomized Phase 3 Study in Patients (Pts) With Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL): Alisertib (MLN8237) Versus Investigator’s Choice (LUMIERE trial; NCT01482962). [No authors listed]Clin Adv Hematol Oncol. 2016 Feb;14(2 Suppl 1):12-3. No abstract available. PMID: 27466629