A-1331852 - CAS 1430844-80-6
Catalog number: B0084-007703
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
Bcl-2 Family
A-1331852, a substituted benzothiazole, is a high affinity BH3 mimetic Ligand of BCL protein BCL-XL (Ki≤ 10 pM). A-1331852 is an orally apoptosis-inducing agent that may have potential as improved cancer therapeutics.
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Catalog Number Size Price Stock Quantity
B0084-007703 100 mg $998 In stock
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Brife Description:
A potent and selective inhibitor of BCL-XL
3-(1-(((3r,5r,7r)-adamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid; A-1331852; A 1331852; A1331852; ABT-263; ABT-199; ABT 199; ABT199
DMSO: ≥ 12 mg/mL
Store in a cool and dry place (or refer to the Certificate of Analysis).
1.50±0.1 g/cm3
Canonical SMILES:
1.Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models.
Punnoose EA;Leverson JD;Peale F;Boghaert ER;Belmont LD;Tan N;Young A;Mitten M;Ingalla E;Darbonne WC;Oleksijew A;Tapang P;Yue P;Oeh J;Lee L;Maiga S;Fairbrother WJ;Amiot M;Souers AJ;Sampath D Mol Cancer Ther. 2016 May;15(5):1132-44. doi: 10.1158/1535-7163.MCT-15-0730. Epub 2016 Mar 3.
BCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, multiple myeloma cells are sensitive to antagonists that selectively target prosurvival proteins such as BCL-2/BCL-XL (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/venetoclax). Resistance to these three drugs is mediated by expression of MCL-1. However, given the selectivity profile of venetoclax it is unclear whether coexpression of BCL-XL also affects antitumor responses to venetoclax in multiple myeloma. In multiple myeloma cell lines (n = 21), BCL-2 is expressed but sensitivity to venetoclax correlated with high BCL-2 and low BCL-XL or MCL-1 expression. Multiple myeloma cells that coexpress BCL-2 and BCL-XL were resistant to venetoclax but sensitive to a BCL-XL-selective inhibitor (A-1155463). Multiple myeloma xenograft models that coexpressed BCL-XL or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by cotreatment with bortezomib in xenografts that coexpressed BCL-2 and MCL-1 due to upregulation of NOXA, a proapoptotic factor that neutralizes MCL-1. In contrast, xenografts that expressed BCL-XL, MCL-1, and BCL-2 were more sensitive to the combination of bortezomib with a BCL-XL selective inhibitor (A-1331852) but not with venetoclax cotreatment when compared with monotherapies.
2.Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.
Leverson JD;Phillips DC;Mitten MJ;Boghaert ER;Diaz D;Tahir SK;Belmont LD;Nimmer P;Xiao Y;Ma XM;Lowes KN;Kovar P;Chen J;Jin S;Smith M;Xue J;Zhang H;Oleksijew A;Magoc TJ;Vaidya KS;Albert DH;Tarrant JM;La N;Wang L;Tao ZF;Wendt MD;Sampath D;Rosenberg SH;Tse C;Huang DC;Fairbrother WJ;Elmore SW;Souers AJ Sci Transl Med. 2015 Mar 18;7(279):279ra40. doi: 10.1126/scitranslmed.aaa4642.
The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax.
3.Selective BH3-mimetics targeting BCL-2, BCL-XL or MCL-1 induce severe mitochondrial perturbations.
Henz K;Al-Zebeeby A;Basoglu M;Fulda S;Cohen GM;Varadarajan S;Vogler M Biol Chem. 2018 Jul 10. pii: /j/bchm.ahead-of-print/hsz-2018-0233/hsz-2018-0233.xml. doi: 10.1515/hsz-2018-0233. [Epub ahead of print]
Induction of apoptosis by selective BH3-mimetics is currently investigated as a novel strategy for cancer treatment. Here, we report that selective BH3-mimetics induce apoptosis in a variety of hematological malignancies. Apoptosis is accompanied by severe mitochondrial toxicities upstream of caspase activation. Specifically, the selective BH3-mimetics ABT-199, A-1331852 and S63845, which target BCL-2, BCL-XL and MCL-1, respectively, induce comparable ultrastructural changes including mitochondrial swelling, a decrease of mitochondrial matrix density and severe loss of cristae structure. These shared effects on mitochondrial morphology indicate a similar function of these anti-apoptotic BCL-2 proteins in maintaining mitochondrial integrity and function.
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CAS 1430844-80-6 A-1331852

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