A-1155463 - CAS 1235034-55-5
Catalog number: B0084-474415
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C35H32FN5O4S2
Molecular Weight:
669.79
COA:
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Targets:
Bcl-2 Family
Description:
A-1155463, an effective and selective BCL-XL inhibitor, has been studied to have probable effect in restraining the growth of small cell lung cancer xenograft tumors. IC50: <0.01 nM (Ki).
Purity:
98%
Appearance:
Powder
Synonyms:
CHEMBL3342332; A-1155463; A 1155463; A1155463; SCHEMBL2501550; BDBM50030754; CS-5398; HY-19725; CS 5398; HY 19725; CS5398; HY19725
Solubility:
DMSO: 31mg/mL
Storage:
-20ºC Freeze
MSDS:
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Application:
A-1155463 is an effective and selective BCL-XL inhibitor that has been studied to have probable effect in restraining the growth of small cell lung cancer xenograft tumors.
Shelf Life:
As supplied, 2 years from the QC date provided on the Certificate of Analysis, when stored properly
Quantity:
Milligrams-Grams
InChIKey:
SOYCFODXNRVBTI-UHFFFAOYSA-N
InChI:
InChI=1S/C35H32FN5O4S2/c1-40(2)17-6-8-22-14-15-28(26(36)20-22)45-19-7-13-30-31(33(43)44)38-35(47-30)41-18-16-23-9-5-10-24(25(23)21-41)32(42)39-34-37-27-11-3-4-12-29(27)46-34/h3-5,9-12,14-15,20H,7,13,16-19,21H2,1-2H3,(H,43,44)(H,37,39,42)
Canonical SMILES:
CN(C)CC#CC1=CC(=C(C=C1)OCCCC2=C(N=C(S2)N3CCC4=CC=CC(=C4C3)C(=O)NC5=NC6=CC=CC=C6S5)C(=O)O)F
1.Exploring the selectivity of inhibitor complexes with Bcl-2 and Bcl-XL: A molecular dynamics simulation approach.
Wakui N;Yoshino R;Yasuo N;Ohue M;Sekijima M J Mol Graph Model. 2018 Jan;79:166-174. doi: 10.1016/j.jmgm.2017.11.011. Epub 2017 Nov 23.
B-cell lymphoma 2 (Bcl-2) family proteins are potential drug targets in cancer and have a relatively flat and flexible binding site. ABT-199 is one of the most promising selective Bcl-2 inhibitors, and A-1155463 selectively inhibits Bcl-XL. Although the amino acid sequences of the binding sites of these two inhibitors are similar, the inhibitors selectively bind the target protein. In order to determine the origin of the selectivity of these inhibitors, we conducted molecular dynamics simulations using protein-inhibitor modeling. We confirmed that ASP103 of Bcl-2 is a key residue and that hydrogen bonding between ASP103 and ABT-199 confers the Bcl-2 selectivity of this inhibitor. For Bcl-XL selectivity, the secondary structure of α-helix 3 is a key factor. PHE105, SER106, and LEU108 in the loose α-helix 3 interact with A-1155463 to confer Bcl-XL selectivity. These findings provide important insights into the molecular mechanisms of selective inhibitors of Bcl-2 family proteins.
2.Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.
Tao ZF;Hasvold L;Wang L;Wang X;Petros AM;Park CH;Boghaert ER;Catron ND;Chen J;Colman PM;Czabotar PE;Deshayes K;Fairbrother WJ;Flygare JA;Hymowitz SG;Jin S;Judge RA;Koehler MF;Kovar PJ;Lessene G;Mitten MJ;Ndubaku CO;Nimmer P;Purkey HE;Oleksijew A;Phillips DC;Sleebs BE;Smith BJ;Smith ML;Tahir SK;Watson KG;Xiao Y;Xue J;Zhang H;Zobel K;Rosenberg SH;Tse C;Leverson JD;Elmore SW;Souers AJ ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93. doi: 10.1021/ml5001867. eCollection 2014 Oct 9.
A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.
3.New agents that target senescent cells: the flavone, fisetin, and the BCL-X
Zhu Y;Doornebal EJ;Pirtskhalava T;Giorgadze N;Wentworth M;Fuhrmann-Stroissnigg H;Niedernhofer LJ;Robbins PD;Tchkonia T;Kirkland JL Aging (Albany NY). 2017 Mar 8;9(3):955-963. doi: 10.18632/aging.101202.
Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in preclinical models. Reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. Here we report that fisetin, a naturally-occurring flavone with low toxicity, and A1331852 and A1155463, selective BCL-X;L; inhibitors that may have less hematological toxicity than the less specific BCL-2 family inhibitor navitoclax, are senolytic. Fisetin selectively induces apoptosis in senescent but not proliferating human umbilical vein endothelial cells (HUVECs). It is not senolytic in senescent IMR90 cells, a human lung fibroblast strain, or primary human preadipocytes. A1331852 and A1155463 are senolytic in HUVECs and IMR90 cells, but not preadipocytes. These agents may be better candidates for eventual translation into clinical interventions than some existing senolytics, such as navitoclax, which is associated with hematological toxicity.
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CAS 1235034-55-5 A-1155463

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