Alisertib
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MedKoo CAT#: 201931

CAS#: 1028486-01-2

Description: Alisertib, also known as 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.


Chemical Structure

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Alisertib
CAS# 1028486-01-2

Theoretical Analysis

MedKoo Cat#: 201931
Name: Alisertib
CAS#: 1028486-01-2
Chemical Formula: C27H20ClFN4O4
Exact Mass: 518.11571
Molecular Weight: 518.9
Elemental Analysis: C, 62.49; H, 3.88; Cl, 6.83; F, 3.66; N, 10.80; O, 12.33

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Related CAS #: 1028486-06-7 (sodium anhydrous)   1208255-63-3 (sodium)  

Synonym: MLN8237; MLN-8237; MLN 8237; alisertib.

IUPAC/Chemical Name: 4-((9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)amino)-2-methoxybenzoic acid

InChi Key: ZLHFILGSQDJULK-UHFFFAOYSA-N

InChi Code: 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)

SMILES Code: O=C(O)C1=CC=C(NC2=NC=C3C(C4=CC=C(Cl)C=C4C(C5=C(OC)C=CC=C5F)=NC3)=N2)C=C1OC

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Alisertib (MLN8237) is a selective Aurora A inhibitor with IC50 of 1.2 nM in a cell-free assay.
In vitro activity: To determine the inhibitory effect of MLN8237 on the mitotic cell population, cell division in MM cell lines was first synchronized by treatment with nocodazole, and then phosphorylation of Aurora-A kinase at threonine 288 (pThr288) was measured by Western blotting. Decreased phosphorylation of Aurora-A kinase was shown in MLN8237-treated MM1.S and OPM1 MM cells (Figure 1B), compared with the DMSO and nocodazole-treated cells. To further analyze inhibition of Aurora-A kinase phosphorylation by MLN8237 in unsynchronized MM cell lines, immunofluorescein staining was performed in MM1.S and OPM1 cells. Costaining with α-tubulin, pAurora-A kinase (Thr288), and 4,6-diamidino-2-phenylindole (nucleus) showed that DMSO-treated MM1.S (Figure 1C) and OPM1 (Figure 1D) cells were proliferating with phosphorylated Aurora-A kinase (Thr288), whereas all MLN8237-treated cells accumulated at the nondividing prometaphase and metaphase stages, with no detectable phosphorylation of Aurora-A kinase. In addition, analysis of DMSO-treated cells by fluorescein microscopy demonstrated ongoing mitosis, within the 15% MM1.S cells and 28.5% OPM-1 cells mitotic cell population expressing pAurora-A kinase (Thr288). Importantly, after 24 hours of MLN8237 treatment, there was an accumulation of prometaphase and metaphase cells, with no detectable expression of pAurora-A kinase (Thr288), in both MM cell lines. In addition, Figure 1E shows that MLN8237 does not inhibit histone H3 phosphorylation at ser10 in these cells, indicating mitosis and active Aurora-B kinase in the MLN8237-treated cells. Reference: Blood. 2010 Jun 24;115(25):5202-13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892955/
In vivo activity: To determine the in vivo antitumor activity of alisertib, mice bearing solid and hematologic human tumor xenografts were administered increasing doses of alisertib. Figure 3A shows average tumor volumes in nude mice bearing subcutaneous HCT-116 tumors after 3 weeks of oral alisertib at 3, 10, or 30 mg/kg once daily. Alisertib treatment resulted in a dose-dependent TGI of 43.3%, 84.2%, and 94.7% for the 3, 10, and 30 mg/kg groups, respectively. The greatest antitumor response in this model was tumor stasis. All doses were well tolerated with the maximum body weight loss of 7.4% in the 30 mg/kg group. As shown in Figure 3B, alisertib treatment in the non-Hodgkin's lymphoma model OCI-LY19 also resulted in tumor regression. Rituximab was used as a control for this model and resulted in moderate antitumor activity when dosed at 10 mg/kg once per week. Alisertib dosed at either 20 mg/kg twice daily or 30 mg/kg once daily resulted in a reduction in luminescent signal below baseline and a TGI of 106% for both groups. Moreover, tumors in the 20 mg/kg dose group did not grow back after more than 60 days of monitoring. Finally, alisertib showed broad antitumor activity across a diverse set of xenograft models, with TGI of greater than 76% at 30 mg/kg in all models tested (Table 3). Reference: Clin Cancer Res. 2011 Dec 15;17(24):7614-24. http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22016509

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 25.0 48.18

Preparing Stock Solutions

The following data is based on the product molecular weight 518.9 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. 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. doi: 10.1182/blood-2009-12-259523. Epub 2010 Apr 9. PMID: 20382844; PMCID: PMC2892955. 2. Manfredi MG, Ecsedy JA, Chakravarty A, Silverman L, Zhang M, Hoar KM, Stroud SG, Chen W, Shinde V, Huck JJ, Wysong DR, Janowick DA, Hyer ML, Leroy PJ, Gershman RE, Silva MD, Germanos MS, Bolen JB, Claiborne CF, Sells TB. Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res. 2011 Dec 15;17(24):7614-24. doi: 10.1158/1078-0432.CCR-11-1536. Epub 2011 Oct 20. PMID: 22016509.
In vivo protocol: 1. 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. doi: 10.1182/blood-2009-12-259523. Epub 2010 Apr 9. PMID: 20382844; PMCID: PMC2892955. 2. Manfredi MG, Ecsedy JA, Chakravarty A, Silverman L, Zhang M, Hoar KM, Stroud SG, Chen W, Shinde V, Huck JJ, Wysong DR, Janowick DA, Hyer ML, Leroy PJ, Gershman RE, Silva MD, Germanos MS, Bolen JB, Claiborne CF, Sells TB. Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res. 2011 Dec 15;17(24):7614-24. doi: 10.1158/1078-0432.CCR-11-1536. Epub 2011 Oct 20. PMID: 22016509.

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.1 Jochems F, Thijssen B, De Conti G, Jansen R, Pogacar Z, Groot K, Wang L, Schepers A, Wang C, Jin H, Beijersbergen RL, Leite de Oliveira R, Wessels LFA, Bernards R. The Cancer SENESCopedia: A delineation of cancer cell senescence. Cell Rep. 2021 Jul 27;36(4):109441. doi: 10.1016/j.celrep.2021.109441. PMID: 34320349.

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. 



Additional Information

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.