MLN8237 (Alisertib)

Aurora A Kinase inhibitor, Potent and selective CAS# 1028486-01-2

MLN8237 (Alisertib)

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Chemical structure

MLN8237 (Alisertib)

3D structure

Chemical Properties of MLN8237 (Alisertib)

Cas No. 1028486-01-2 SDF Download SDF
PubChem ID 24771867 Appearance Powder
Formula C27H20ClFN4O4 M.Wt 518.92
Type of Compound N/A Storage Desiccate at -20°C
Synonyms MLN 8237
Solubility DMSO : 41.67 mg/mL (80.30 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid
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
Standard InChIKey ZLHFILGSQDJULK-UHFFFAOYSA-N
Standard 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)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of MLN8237 (Alisertib)

DescriptionAlisertib (MLN8237) is a selective inhibitor of Aurora A with IC50 of 1.2 nM. It has >200-fold higher selectivity for Aurora A than Aurora B.
TargetsAurora A    
IC501.2 nM     

Protocol

Cell experiment: [1]

Cell lines

TIB-48 and CRL-2396 cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

>100 nM, 48 hours

Applications

TIB-48 and CRL-2396 cells were treated with MLN8237 at 10 nM, 50 nM, 100 nM, 500 nM and 1.0 μ M for 48 h. MLN8237 induced apoptosis at concentrations >100 nM, suggesting that induction of apoptosis is dose-dependent. These results were confirmed by demonstrating an increased level of cleaved PARP in treated TIB-48 and CRL-2396 cells. PARP cleavage was observed even at the concentration of MLN8237 as low as 50 nM.

Animal experiment: [2]

Animal models

Female C.B-17 SCID mice injected with OVCAR-5-pWZL-Luc cells

Dosage form

Oral administration, 20 or 30 mg/kg, once daily (QD) or twice daily (BID)

Application

The mice (n=16/group) were randomly divided into five treatment groups: 1) vehicle, 2) 20 mg/kg alisertib, 3) 30 mg/kg alisertib, 4) 5 mg/kg paclitaxel and 5) 20 mg/kg alisertib + 5 mg/kg paclitaxel. Tumor growth was monitored by weekly BLI and the log-transformed total flux data showed significantly decreased tumor growth rates in mice treated with alisertib (20 or 30 mg/kg) compared to vehicle-treated mice. Treatment with 20 mg/kg and 30 mg/kg alisertib resulted in 51% and 49% TGI, respectively.

her notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Qi W, Spier C, Liu X, et al. Alisertib (MLN8237) an investigational agent suppresses Aurora A and B activity, inhibits proliferation, promotes endo-reduplication and induces apoptosis in T-NHL cell lines supporting its importance in PTCL treatment. Leukemia research, 2013, 37(4): 434-439.

[2] Do T V, Xiao F, Bickel L E, et al. Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion. Oncogene, 2013, 33(5): 539-549.

MLN8237 (Alisertib) Dilution Calculator

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MLN8237 (Alisertib) Molarity Calculator

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Preparing Stock Solutions of MLN8237 (Alisertib)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9271 mL 9.6354 mL 19.2708 mL 38.5416 mL 48.177 mL
5 mM 0.3854 mL 1.9271 mL 3.8542 mL 7.7083 mL 9.6354 mL
10 mM 0.1927 mL 0.9635 mL 1.9271 mL 3.8542 mL 4.8177 mL
50 mM 0.0385 mL 0.1927 mL 0.3854 mL 0.7708 mL 0.9635 mL
100 mM 0.0193 mL 0.0964 mL 0.1927 mL 0.3854 mL 0.4818 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of MLN8237 (Alisertib)

1. Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines. Invest New Drugs. 2013 Feb;31(1):39-45. doi: 10.1007/s10637-012-9831-9. Epub 2012 Jun 6.
Abstract
The combination of vorinsostat and MLN8237, a Aurora A kinase inhibitor, has the potential to exhibit enhanced antitumor activity against pediatric tumor cell lines through disrupting the spindle assembly and the mitotic checkpoint.
4. Phase I study of MLN8237-investigational Aurora A kinase inhibitor-in relapsed/refractory multiple myeloma, Non-Hodgkin lymphoma and chronic lymphocytic leukemia. Invest New Drugs. 2013 Dec 20. [Epub ahead of print]
Abstract
MLN8237 exhibited modest activity with the maximum tolerated dose of 50 mg BID on the ECT 7-day schedule and the terminal half-life of 19 hours in a phase I study evaluating two regimes of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies, in which MLN8237 ECT of 50 mg BID for 7 days in 21-day cycles is recommended.

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Background on MLN8237 (Alisertib)

The orally bioavailable agent, MLN8237 (also known as alisertib), is a potent small-molecule inhibitor of Aurora A kinase (AAK) which is overexpressed in several types of tumor and  associated with oncogenesis and tumor progression. It was developed from its predecessor, MLN8054, in order to minimize the benzodiazepine-like effects seen with MLN8054. The inhibitory effect of MLN8237 is ATP-competitive, reversible and AAK-specific with an inhibition constant (Ki) of 0.43 nmol/L. MLN8237 is being investigated to treat advanced malignancies, due to its both in vitro and in vivo activities against a broad range of tumor types.

Reference

E. Claire Dees, Roger B. Cohen, Margaret von Mehren, Thomas E. Stinchcombe, Hua Liu, Karthik Venkatakrishnan, Mark Manfredi, Howard Fingert, Howard A. Burris III, and Jeffrey R. Infante. Phase I study of aurora A kniase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res 2012; 18:4775-4784.

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References on MLN8237 (Alisertib)

Phase II study of MLN8237 (Alisertib) in advanced/metastatic sarcoma.[Pubmed:27502708]

Ann Oncol. 2016 Oct;27(10):1855-60.

BACKGROUND: Aurora kinase A (AURKA) is commonly overexpressed in sarcoma. The inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (Alisertib) is a novel oral adenosine triphosphate-competitive AURKA inhibitor. PATIENTS AND METHODS: This Cancer Therapy Evaluation Program-sponsored phase II study of alisertib was conducted through the Alliance for Clinical Trials in Oncology (A091102). Patients were enrolled into histology-defined cohorts: (i) liposarcoma, (ii) leiomyosarcoma, (iii) undifferentiated sarcoma, (iv) malignant peripheral nerve sheath tumor, or (v) other. Treatment was alisertib 50 mg PO b.i.d. d1-d7 every 21 days. The primary end point was response rate; progression-free survival (PFS) was secondary. One response in the first 9 patients expanded enrollment in a cohort to 24 using a Simon two-stage design. RESULTS: Seventy-two patients were enrolled at 24 sites [12 LPS, 10 LMS, 11 US, 10 malignant peripheral nerve sheath tumor (MPNST), 29 Other]. The median age was 55 years; 54% were male; 58%/38%/4% were ECOG PS 0/1/2. One PR expanded enrollment to the second stage in the other sarcoma cohort. The histology-specific cohorts ceased at the first stage. There were two confirmed PRs in the other cohort (both angiosarcoma) and one unconfirmed PR in dedifferentiated chondrosarcoma. Twelve-week PFS was 73% (LPS), 44% (LMS), 36% (US), 60% (MPNST), and 38% (Other). Grade 3-4 adverse events: oral mucositis (12%), anemia (14%), platelet count decreased (14%), leukopenia (22%), and neutropenia (42%). CONCLUSIONS: Alisertib was well tolerated. Occasional responses, yet prolonged stable disease, were observed. Although failing to meet the primary RR end point, PFS was promising. TRIAL REGISTRATION ID: NCT01653028.

A phase 2 study of alisertib (MLN8237) in recurrent or persistent uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group study 0231D.[Pubmed:28094040]

Gynecol Oncol. 2017 Jan;144(1):96-100.

OBJECTIVE: This two-stage Phase II study assessed the activity of single agent alisertib in patients with recurrent/persistent uterine leiomyosarcoma (uLMS). METHODS: Eligibility criteria included histologically-confirmed, recurrent or persistent uLMS, age>/=18, 1-2 prior cytotoxic regimens, and RECIST version 1.1 measurable disease. The primary objective of the study was to evaluate the efficacy of alisertib through the frequency of patients with objective tumor responses and the frequency who survived event-free for at least 6months (EFS6). The endpoints for EFS were RECIST progression, death, or beginning a subsequent therapy. The null hypothesis jointly specified the probability of a patient experiencing a tumor response to less than or equal to 5% and the probability of a patient surviving event-free for at least 6months to less than or equal to 20%. A two-stage design was used with a target accrual of 23 patients for stage 1 and 47 pts. cumulative for stage 2. Confidence intervals do not correct for multiplicity. RESULTS: Twenty-three patients were enrolled with two patients excluded on central histology review, yielding 21 eligible patients. Median age was 61years. Prior treatment was either 1 cytotoxic regimen (71.4%) or 2 (28.6%). The most common treatment related AEs (grade 3 or worse) were anemia Hensley et al. (2008a) , leukopenia Hensley et al. (2008b) , neutropenia Maki et al. (2007) , thrombocytopenia Huang et al. (2012) , mucositis Hensley et al. (2008a) , diarrhea Huang et al. (2012) , and palmer-planter syndrome Zivanovic et al. (2012) . There were no objective responses (0%; 90% CI: 0-10.4%). Best response was stable disease (38.1%); 12 patients had progressive disease (57.1%). EFS6 was 0% (90% CI: 0-10.4%). Median PFS and OS were 1.7 (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.6 - NA), respectively. CONCLUSION: Alisertib did not demonstrate clinically meaningful single agent activity in previously treated uLMS.

Open-label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors.[Pubmed:27192055]

Cancer. 2016 Aug 15;122(16):2524-33.

BACKGROUND: This study was designed to determine the safety, tolerability, and pharmacokinetics (PK) of alisertib (MLN8237) in combination with docetaxel and to identify a recommended dose for the combination. METHODS: Adults with metastatic cancer were treated on 21-day cycles with alisertib (10, 20, 30, or 40 mg) twice daily on days 1 to 7 or days 1 to 5 and with docetaxel (75 or 60 mg/m(2) ) on day 1. The primary objectives were to assess the safety and tolerability of the combination and to determine the recommended phase 2 dose (RP2D) for future studies. Secondary objectives included an efficacy assessment and PK analyses of docetaxel and alisertib. RESULTS: Forty-one patients participated. Eight dose levels were explored with various doses of alisertib and docetaxel. The dose-limiting toxicities were neutropenic fever, neutropenia without fever, stomatitis, and urinary tract infection. The RP2D of this combination was 20 mg of alisertib twice daily on days 1 to 7 and intravenous docetaxel at 75 mg/m(2) on day 1 in 21-day cycles. Eight of the 28 patients (29%) who were efficacy-evaluable had objective responses. These included 1 complete response in a patient with bladder cancer, 6 partial responses in patients with castration-resistant prostate cancer, and 1 partial response in a patient with angiosarcoma. Concomitant administration of alisertib did not produce any clinically meaningful change in docetaxel PK. CONCLUSIONS: Alisertib at 20 mg twice daily on days 1 to 7 with intravenous docetaxel at 75 mg/m(2) on day 1 in a 21-day cycle was well tolerated, and the combination demonstrated antitumor activity. Cancer 2016;122:2524-33. (c) 2016 American Cancer Society.

Description

Alisertib (MLN 8237) is an orally active and selective Aurora A kinase inhibitor (IC50=1.2 nM), which binds to Aurora A kinase resulting in mitotic spindle abnormalities, mitotic accumulation. Alisertib (MLN 8237) induces apoptosis and autophagy through targeting the AKT/mTOR/AMPK/p38 pathway in leukemic cells. Antitumor activity.

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