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 Alisertib

Description of Alisertib (MLN8237): MLN8237  is a second-generation, orally bioavailable, highly selective small molecule inhibitor of the serine/threonine protein kinase Aurora A kinase with potential antineoplastic activity. Aurora kinase inhibitor MLN8237 binds to and inhibits Aurora A kinase, which may result in disruption of the assembly of the mitotic spindle apparatus, disruption of chromosome segregation, and inhibition of cell proliferation. Aurora A kinase localizes to the spindle poles and to spindle microtubules during mitosis, and is thought to regulate spindle assembly. Aberrant expression of Aurora kinases occurs in a wide variety of cancers, including colon and breast cancers. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

MLN-8237 is an Aurora A kinase blocker designed to disrupt the cycle of cancer cells. It
is being tested in several types of cancer as monotherapy and in combination with different
chemotherapy regimens. Millennium expects MLN-8237 to progress to mid-stage trials later in
2009. If MLN-8237 survives the clinical trial process, it may become the first approved therapy
in the Aurora A kinase blocker class. Millennium is in a race, however, with research and development divisions at other pharmaceutical companies that are testing their own Aurora A kinase blockers. see: www.hcplive.com/media/pdf/May09_09PFN.pdf .

 Current developer:   Millennium Pharmaceuticals, Inc.

1. Preparation of [(phenylpyrimidobenzazepinyl)amino]methoxybenzoic acid derivatives for us as antitumor agents. Claiborne, Christopher F.; Sells, Todd B.; Stroud, Stephen G. (Millennium Pharmaceuticals, Inc., USA). PCT Int. Appl. (2008), 43pp. CODEN: PIXXD2 WO 2008063525 A1 20080529 . Patent written in English. Application: WO 2007-US23948 20071114. Priority: US 2006-859340 20061116. 

1: Lipsitz E, Moorthy G, Mosse Y, Fox E, Adamson PC. A sensitive and selective liquid chromatography/tandem mass spectrometry method for determination of MLN8237 in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Sep 1;878(25):2369-73. Epub 2010 Jul 3. PubMed PMID: 20685183; PubMed Central PMCID: PMC2940716.

2: Kovar H. AURKA inhibitors: right in time. Pediatr Blood Cancer. 2010 Jul 15;55(1):3-4. PubMed PMID: 20486161.

3: Sloane DA, Trikic MZ, Chu ML, Lamers MB, Mason CS, Mueller I, Savory WJ, Williams DH, Eyers PA. Drug-resistant aurora A mutants for cellular target validation of the small molecule kinase inhibitors MLN8054 and MLN8237. ACS Chem Biol. 2010 Jun 18;5(6):563-76. PubMed PMID: 20426425.

4: Görgün G, Calabrese E, Hideshima T, Ecsedy J, Perrone G, Mani M, Ikeda H, Bianchi G, Hu Y, Cirstea D, Santo L, Tai YT, Nahar S, Zheng M, Bandi M, Carrasco RD, Raje N, Munshi N, Richardson P, Anderson KC. A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood. 2010 Jun 24;115(25):5202-13. Epub 2010 Apr 9. PubMed PMID: 20382844; PubMed Central PMCID: PMC2892955.

5: Tomita M, Mori N. Aurora A selective inhibitor MLN8237 suppresses the growth and survival of HTLV-1-infected T-cells in vitro. Cancer Sci. 2010 May;101(5):1204-11. Epub 2010 Jan 19. PubMed PMID: 20180813.

6: Maris JM, Morton CL, Gorlick R, Kolb EA, Lock R, Carol H, Keir ST, Reynolds CP, Kang MH, Wu J, Smith MA, Houghton PJ. Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP). Pediatr Blood Cancer. 2010 Jul 15;55(1):26-34. PubMed PMID: 20108338; PubMed Central PMCID: PMC2874079.