Alisertib | CAS#1028486-01-2 | Aurora A inhibitor

MedKoo Cat#: 201931 | Name: Alisertib

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Alisertib (MLN8237) is a selective, small-molecule inhibitor of Aurora A kinase (AURKA), a serine/threonine kinase critical for mitotic entry, centrosome maturation, and spindle assembly. It exhibits potent in vitro activity with an IC₅₀ of approximately 1.2 nM against AURKA, while showing over 200-fold selectivity versus Aurora B and C kinases. In cellular assays, alisertib induces mitotic spindle abnormalities, leading to G2/M cell cycle arrest and subsequent apoptosis in cancer cells. Preclinical studies have demonstrated nanomolar antiproliferative activity in a broad range of tumor cell lines, including neuroblastoma, breast, colorectal, and hematologic malignancies, with in vivo tumor regression observed in xenograft models at doses of 10–30 mg/kg.

Chemical Structure

Alisertib

CAS#1028486-01-2 (free acid)

Theoretical Analysis

MedKoo Cat#: 201931

Name: Alisertib

CAS#: 1028486-01-2 (free acid)

Chemical Formula: C27H20ClFN4O4

Exact Mass: 518.1157

Molecular Weight: 518.90

Elemental Analysis: C, 62.49; H, 3.88; Cl, 6.83; F, 3.66; N, 10.80; O, 12.33

Price and Availability

Size	Price	Availability
10mg	USD 90.00	Ready to ship
25mg	USD 150.00	Ready to ship
50mg	USD 250.00	Ready to ship
100mg	USD 450.00	Ready to ship
200mg	USD 750.00	Ready to ship

Bulk Inquiry

Buy Now

Add to Cart

Related CAS #

1028486-01-2 (free acid) 1028486-06-7 (sodium) 1208255-63-3 (sodium hydrate)

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

More Info

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.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#T21D03P03

QC Data

View QC data: current batch, Lot#T21D03P03

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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

	Solvent	mg/mL	mM
Solubility
	DMSO	25.0	48.18

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 518.90 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.

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

Formulation protocol:

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: Beltran H, Oromendia C, Danila DC, Montgomery B, Hoimes C, Szmulewitz RZ, Vaishampayan U, Armstrong AJ, Stein M, Pinski J, Mosquera JM, Sailer V, Bareja R, Romanel A, Gumpeni N, Sboner A, Dardenne E, Puca L, Prandi D, Rubin MA, Scher HI, Rickman DS, Demichelis F, Nanus DM, Ballman KV, Tagawa ST. A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration- resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers. Clin Cancer Res. 2019 Jan 1;25(1):43-51. doi: 10.1158/1078-0432.CCR-18-1912. Epub 2018 Sep 19. PMID: 30232224; PMCID: PMC6320304. 2: Liewer S, Huddleston A. Alisertib: a review of pharmacokinetics, efficacy and toxicity in patients with hematologic malignancies and solid tumors. Expert Opin Investig Drugs. 2018 Jan;27(1):105-112. doi: 10.1080/13543784.2018.1417382. Epub 2018 Jan 3. PMID: 29260599. 3: Vagiannis D, Zhang Y, Budagaga Y, Novotna E, Skarka A, Kammerer S, Küpper JH, Hofman J. Alisertib shows negligible potential for perpetrating pharmacokinetic drug-drug interactions on ABCB1, ABCG2 and cytochromes P450, but acts as dual- activity resistance modulator through the inhibition of ABCC1 transporter. Toxicol Appl Pharmacol. 2022 Jan 1;434:115823. doi: 10.1016/j.taap.2021.115823. Epub 2021 Dec 9. PMID: 34896433. 4: Tremblay D, Mascarenhas J. Next Generation Therapeutics for the Treatment of Myelofibrosis. Cells. 2021 Apr 27;10(5):1034. doi: 10.3390/cells10051034. PMID: 33925695; PMCID: PMC8146033. 5: Alrifai D, Pettengell R. MLN8237 ( alisertib ) and its role in peripheral T-cell lymphoma. Expert Opin Investig Drugs. 2014 Dec;23(12):1731-6. doi: 10.1517/13543784.2014.972501. Epub 2014 Oct 17. PMID: 25323772. 6: Gallop-Evans E. The role of alisertib in treatment of peripheral T-cell lymphomas. Future Oncol. 2015 Sep;11(18):2515-24. doi: 10.2217/fon.15.154. Epub 2015 Sep 7. PMID: 26344156. 7: 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; PMCID: PMC8333195. 8: Thomas X. Alisertib: a new option for acute myeloid leukaemia. Lancet Haematol. 2020 Feb;7(2):e87-e88. doi: 10.1016/S2352-3026(19)30215-7. Epub 2019 Dec 11. PMID: 31837958. 9: Durlacher CT, Li ZL, Chen XW, He ZX, Zhou SF. An update on the pharmacokinetics and pharmacodynamics of alisertib, a selective Aurora kinase A inhibitor. Clin Exp Pharmacol Physiol. 2016 Jun;43(6):585-601. doi: 10.1111/1440-1681.12571. PMID: 26999067. 10: Shah N, Mohammad AS, Saralkar P, Sprowls SA, Vickers SD, John D, Tallman RM, Lucke-Wold BP, Jarrell KE, Pinti M, Nolan RL, Lockman PR. Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases. Pharmacol Res. 2018 Jun;132:47-68. doi: 10.1016/j.phrs.2018.03.021. Epub 2018 Mar 28. PMID: 29604436; PMCID: PMC5997530. 11: Niu H, Manfredi M, Ecsedy JA. Scientific Rationale Supporting the Clinical Development Strategy for the Investigational Aurora A Kinase Inhibitor Alisertib in Cancer. Front Oncol. 2015 Aug 24;5:189. doi: 10.3389/fonc.2015.00189. PMID: 26380220; PMCID: PMC4547019. 12: Tayyar Y, Jubair L, Fallaha S, McMillan NAJ. Critical risk-benefit assessment of the novel anti-cancer aurora a kinase inhibitor alisertib (MLN8237): A comprehensive review of the clinical data. Crit Rev Oncol Hematol. 2017 Nov;119:59-65. doi: 10.1016/j.critrevonc.2017.09.006. Epub 2017 Sep 18. PMID: 29065986. 13: Zhou X, Mould DR, Yuan Y, Fox E, Greengard E, Faller DV, Venkatakrishnan K. Population Pharmacokinetics and Exposure-Safety Relationships of Alisertib in Children and Adolescents With Advanced Malignancies. J Clin Pharmacol. 2022 Feb;62(2):206-219. doi: 10.1002/jcph.1958. Epub 2022 Jan 15. PMID: 34435684; PMCID: PMC9274904. 14: Bradley CA. Correlates of alisertib response. Nat Rev Urol. 2018 Dec;15(12):726. doi: 10.1038/s41585-018-0107-9. PMID: 30315210. 15: Nguyen R, Wang H, Sun M, Lee DG, Peng J, Thiele CJ. Combining selinexor with alisertib to target the p53 pathway in neuroblastoma. Neoplasia. 2022 Apr;26:100776. doi: 10.1016/j.neo.2022.100776. Epub 2022 Feb 23. PMID: 35217309; PMCID: PMC8866064. 16: Wetmore C, Boyett J, Li S, Lin T, Bendel A, Gajjar A, Orr BA. Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children. Neuro Oncol. 2015 Jun;17(6):882-8. doi: 10.1093/neuonc/nov017. Epub 2015 Feb 16. PMID: 25688119; PMCID: PMC4483126. 17: Dardenne E, Beltran H, Benelli M, Gayvert K, Berger A, Puca L, Cyrta J, Sboner A, Noorzad Z, MacDonald T, Cheung C, Yuen KS, Gao D, Chen Y, Eilers M, Mosquera JM, Robinson BD, Elemento O, Rubin MA, Demichelis F, Rickman DS. N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer. Cancer Cell. 2016 Oct 10;30(4):563-577. doi: 10.1016/j.ccell.2016.09.005. PMID: 27728805; PMCID: PMC5540451. 18: Tomao F, Benedetti Panici P, Tomao S. Paclitaxel and Alisertib in Recurrent Ovarian Cancer. JAMA Oncol. 2019 Jun 1;5(6):909-910. doi: 10.1001/jamaoncol.2019.0559. PMID: 31021384. 19: Falchook G, Coleman RL, Roszak A, Behbakht K, Matulonis U, Ray-Coquard I, Sawrycki P, Duska LR, Tew W, Ghamande S, Lesoin A, Schwartz PE, Buscema J, Fabbro M, Lortholary A, Goff B, Kurzrock R, Martin LP, Gray HJ, Fu S, Sheldon- Waniga E, Lin HM, Venkatakrishnan K, Zhou X, Leonard EJ, Schilder RJ. Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):e183773. doi: 10.1001/jamaoncol.2018.3773. Epub 2019 Jan 10. PMID: 30347019; PMCID: PMC6439781. 20: Chen Y, Liu R, Wang W, Wang C, Zhang N, Shao X, He Q, Ying M. Advances in targeted therapy for osteosarcoma based on molecular classification. Pharmacol Res. 2021 Jul;169:105684. doi: 10.1016/j.phrs.2021.105684. Epub 2021 May 19. PMID: 34022396.

.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.