Posted: Friday, April 29, 2022
BCL2 inhibitors were shown to have in vitro antilymphoma activity in both diffuse large B-cell lymphoma (DLBCL) and splenic marginal zone lymphoma cells with acquired resistance to the kinase inhibitors idelalisib, copanlisib, or ibrutinib. Afua Adjeiwaa Mensah, PhD, of the Institute of Oncology Research at the Università della Svizzera Italiana in Bellinzona, Switzerland, presented this research on behalf of colleagues at the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 3942/16).
“Our results suggest that these compounds are structures further exploitable for the design of improved antilymphoma drugs,” concluded the authors.
Researchers used an in silico–based drug design as well as classical and kinetic target–guided synthesis to create seven potential BCL2 inhibitors. The antiproliferative activity of these BCL2 inhibitors was assessed in one BCL2-amplified DLBCL line, six BCL2-translocated DLBCLs, and one resistant splenic marginal zone lymphoma cell line. The cells were treated with increasing concentrations of the BCL2 inhibitors for 72 hours.
The median inhibitory concentration (IC50) values for the seven BCL2 inhibitors ranged from 22 µM to 49 µM. The most potent inhibitor was ST-65 (median IC50 = 22 µM), showing antiproliferative activity in the DLBCL lines and in the splenic marginal zone lymphoma line. The other inhibitors were inactive in at least two of the tested cell lines. Notably, ST-65 was the only BCL2 inhibitor to use kinetic target–guided synthesis, indicating this may be a superior technique for creation of these inhibitors. The three least potent BCL2 inhibitors had IC50s of 49, 44, and 45 µM, respectively. One of these inhibitors was noted to be unable to cross the cell membrane, explaining its poor activity.
The activated B-cell–like DLBCL line was sensitive only to ST-65, with an IC50 of 20 µM. This cell line lacked translocated BCL2, but BCL2 was amplified and overexpressed in these cells.
Disclosure: For a full list of authors’ disclosures, visit abstractsonline.com.