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Bcl-2&P53

A-1210477 (1668553-26-1)

A-1210477 is a potent and selective MCL-1 inhibitor with Ki and IC50 of 0.454 nM and 26.2 nM, respectively, >100-fold selectivity over other Bcl-2 family members…

Not Intended for Therapeutic Use. For research use only.

CAS: 1668553-26-1 Category

A-1210477 (1668553-26-1) Description:

A-1210477 is a potent and selective MCL-1 inhibitor. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines. A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. A-1210477 is a potential therapeutics for the treatment of cancer. The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target.

A-1210477 is an effective and specific MCL-1 inhibitor with an EC50 value below 5 µmol/L  Selectively, it binds to MCL-1 with an affinity of 0.45 nM.

In MCL-1-dependent SVEC cells, treatment with A-1210477 at varying doses, induced cell death in a dose-dependent manner. SYTOX Green exclusion and live-cell imaging were used to determine cell viability. In line with increased potency, cell death was more rapidly induced by A-1210477. To examine the selectivity of A-1210477 for targeting Bcl-2 family members, BcL-xL-, BcL-2-, and MCL-1-dependent SVEC cells were treated with A-1210477. A-1210477 only killed MCL-1-dependent cells. Compared with UMI-77, A-1210477 showed greater potency and specificity as an MCL-1 inhibitor, the EC50 value of UMI-77 is 10 µmol/L. In living cells, A-1210477 disrupted BIM/MCL-1 complexes. In MCL-1-dependent cancer cells, A-1210477 induced the hallmarks of mitochondrial apoptosis. In various malignant cell lines, A-1210477 induced apoptosis, synergizing with navitoclax. Data also demonstrate that A-1210477 acted through an on-target mechanism. It appeared as the first BH3 mimetic targeting MCL-1.

The pharmacokinetics of A-1210477 are not favorable for in vivo use.

A-1210477 (1668553-26-1) Specifications:

Product Name A-1210477
Synonym A-1210477; A 1210477; A1210477.
Chemical Name 7-(5-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1-yl)phenoxy)methyl)-1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-morpholinoethyl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
Drug Class  
Purity >98% (or refer to the Certificate of Analysis)
CAS Number 1668553-26-1
Molecular Formula C46H55N7O7S
Molecular Weight 850.05
Monoisotopic Mass
849.388 g/mol

 

MDL number N/A
InChIKey XMVAWGSQPHFXKU-UHFFFAOYSA-N
InChi Code InChI=1S/C46H55N7O7S/c1-33-43(41(49(4)47-33)32-60-36-19-17-35(18-20-36)51-22-24-52(25-23-51)61(56,57)48(2)3)40-14-8-13-38-39(15-9-29-59-42-16-7-11-34-10-5-6-12-37(34)42)45(46(54)55)53(44(38)40)26-21-50-27-30-58-31-28-50/h5-8,10-14,16-20H,9,15,21-32H2,1-4H3,(H,54,55)
SMILES O=C(C(N1CCN2CCOCC2)=C(CCCOC3=C(C=CC=C4)C4=CC=C3)C5=C1C(C6=C(COC7=CC=C(N8CCN(S(=O)(N(C)C)=O)CC8)C=C7)N(C)N=C6C)=CC=C5)O
Form Solid powder
Color N/A
Solubility  Soluble in DMSO, not in water
Storage Temp.  Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).
Shelf life >2 years if stored properly
Handling Protect from air and moisture
Application In H929 cells, A-1210477 bound selectively and strongly to MCL-1, and reduced the amount of BIM co-immunoprecipitated with MCL-1 in a dose-dependent manner with an IC50 value in the low-μM range.

 


RIDADR NONH for all modes of transport

References:

[1]. Xiao Y, Nimmer P, Sheppard GS, Bruncko M, Hessler P, Lu X, Roberts-Rapp L, Pappano WN, Elmore SW, Souers AJ, Leverson JD, Phillips DC. MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor. Mol Cancer Ther. 2015 Aug;14(8):1837-47. doi: 10.1158/1535-7163.MCT-14-0928. Epub 2015 May 26. PubMed PMID: 26013319.

[2]. Leverson JD, Zhang H, Chen J, Tahir SK, Phillips DC, Xue J, Nimmer P, Jin S, Smith M, Xiao Y, Kovar P, Tanaka A, Bruncko M, Sheppard GS, Wang L, Gierke S, Kategaya L, Anderson DJ, Wong C, Eastham-Anderson J, Ludlam MJ, Sampath D, Fairbrother WJ, Wertz I, Rosenberg SH, Tse C, Elmore SW, Souers AJ. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis. 2015 Jan 15;6:e1590. doi: 10.1038/cddis.2014.561. PubMed PMID: 25590800.

[3].Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Fiskus W, Cai T, DiNardo CD, Kornblau SM, Borthakur G, Kadia TM, Pemmaraju N, Bose P, Masarova L, Rajapakshe K, Perera D, Coarfa C, Mill CP, Saenz DT, Saenz DN, Sun B, Khoury JD, Shen Y, Konopleva M, Bhalla KN. Blood Cancer J. 2019 Jan 15;9(2):4. doi: 10.1038/s41408-018-0165-5.

[4]. MCL-1 or BCL-xL-dependent resistance to the BCL-2 antagonist (ABT-199) can be overcome by specific inhibitor as single agents and in combination with ABT-199 in acute myeloid leukemia cells. Wang Q, Wan J, Zhang W, Hao S. Leuk Lymphoma. 2019 Jan 10:1-11. doi: 10.1080/10428194.2018.1563694. [Epub ahead of print]

[5]. Targeting Mcl-1 inhibits survival and self-renewal of hepatocellular cancer stem-like cells. Zhang H, Li G, Chen G, Zhang Y, Pan J, Tang H, Li J, Guo W, Zhang S. Clin Res Hepatol Gastroenterol. 2018 Dec 5. pii: S2210-7401(18)30261-4. doi: 10.1016/j.clinre.2018.11.004. [Epub ahead of print]