BCL2 inhibitor ABT-199

ABT-199(venetoclax, RG7601, GDC-0199) is a new selective small molecule inhibitor of BCL-2 that appears to spare platelets while achieving potent antitumor activity.

Aberrant over-expression of BCL-2 family proteins (BCL-2, BCL-xL, MCL-1) are associated with hematological malignancies. ABT-199 is specific for BCL-2 and induces selective death of BCL-2 dependent tumor cells while sparing platelets.

Bioactivity

In this study, OCI-AML3 cells and U937 cells were resistant to BCL-2-selective inhibitor ABT-199 in vitro and in vivo, however, while OCI-AML3 cells were sensitive to MCL-1-selective inhibitor A-1210477 in vitro and in vivo, indicating that A-1210477 could counteract the resistance of AML cells to ABT-199 as a single agent in MCL-1-dependent AML cells. U-937 cell line and mouse model were resistant to A-1210477 or ABT-199, and expressed high level of BCL-xL, indicating that BCL-xL might play an important role in the resistance of A-1210477 or ABT-199. Besides, this study also showed that ABT-199 could synergize with A-1210477 in vitro or in vivo.

With the advent of new agents targeting CD20, Bruton’s tyrosine kinase, and phosphoinositol-3 kinase for chronic lymphoid leukemia (CLL), more treatment options exist than ever before. B-cell lymphoma-2 (BCL-2) plays a major role in cellular apoptosis and is a druggable target. Small molecule inhibitors of BCL-2 are in active clinical studies. ABT-199 (venetoclax, RG7601, GDC-0199) has been granted breakthrough designation by FDA for relapsed or refractory CLL with 17p deletion.

Reference

[1] SHUNDONG CANG. ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development.[J]. Journal of Hematology & Oncology, 2015, 8 1: 129. DOI:10.1186/s13045-015-0224-3.

[2] MATTHEW S DAVIDS   Anthony L. ABT-199: taking dead aim at BCL-2.[J]. Cancer Cell, 2013, 23 2: 139-141. DOI:10.1016/j.ccr.2013.01.018.

[3] QING WANG. 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.[J]. Leukemia & Lymphoma, 2019, 60 9: 2170-2180. DOI:10.1080/10428194.2018.1563694.