biostudies-literatureHe YDeutsche ForschungsgemeinschaftNCI NIH HHSNational Institutes of HealthNIH HHSLeukemia and Lymphoma Society95https://www.ebi.ac.uk/biostudies/studies/S-EPMC7364785biostudies-literatureUnknown13(1)<h4>Background</h4>Patients with advanced T cell lymphomas (TCLs) have limited therapeutic options and poor outcomes in part because their TCLs evade apoptosis through upregulation of anti-apoptotic Bcl-2 proteins. Subsets of TCL cell lines, patient-derived xenografts (PDXs), and primary patient samples depend on Bcl-xL for survival. However, small molecule Bcl-xL inhibitors such as ABT263 have failed during clinical development due to on-target and dose-limiting thrombocytopenia.<h4>Methods</h4>We have developed DT2216, a proteolysis targeting chimera (PROTAC) targeting Bcl-xL for degradation via Von Hippel-Lindau (VHL) E3 ligase, and shown that it has better anti-tumor activity but is less toxic to platelets compared to ABT263. Here, we examined the therapeutic potential of DT2216 for TCJournal of hematology & oncologyDT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas.PMC7364785R01CA219836R01 CA242003R01CA241191R35 CA231958R35CA239158R01 CA219836#7011-16R21CA223371R01CA211963R01 CA211963R01CA242003KO 4627/2-1Wiegand JSLv DOrtiz YTWeinstock DMZhang PLi WThummuri DHe YZhang XZhou DPalmer ACBudamagunta VZheng GKoch RKhan SfalseDT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas.<h4>Background</h4>Patients with advanced T cell lymphomas (TCLs) have limited therapeutic options and poor outcomes in part because their TCLs evade apoptosis through upregulation of anti-apoptotic Bcl-2 proteins. Subsets of TCL cell lines, patient-derived xenografts (PDXs), and primary patient samples depend on Bcl-xL for survival. However, small molecule Bcl-xL inhibitors such as ABT263 have failed during clinical development due to on-target and dose-limiting thrombocytopenia.<h4>Methods</h4>We have developed DT2216, a proteolysis targeting chimera (PROTAC) targeting Bcl-xL for degradation via Von Hippel-Lindau (VHL) E3 ligase, and shown that it has better anti-tumor activity but is less toxic to platelets compared to ABT263. Here, we examined the therapeutic potential of DT2216 for TC2020-01-01T00:00:00Z2020 Jul2025-04-04T20:16:52.465Z2025-04-04T20:16:52.465ZS-EPMC73647853267797610.1186/s13045-020-00928-9