DT2216

DT2216 is a proteolysis-targeting chimera (PROTAC) composed of the Bcl-2 family inhibitor ABT-263 (Item No. 11500) conjugated to a von Hippel-Lindau (VHL) E3 ligase ligand.¹ It selectively induces degradation of Bcl-xL in MOLT-4 T cell acute lymphoblastic leukemia (T-ALL) cells with a 50% degradation concentration (DC₅₀) value of 63 nM and maximum degradation (D_max) of 90.8% over washed isolated human platelets with a D_max of 26% at 3 µM. DT2216 selectively binds to Bcl-xL and Bcl-2 over Bcl-W (K_is = 12.82, 1.82, and 300.9 nM, respectively) but does not induce degradation of Bcl-2 or Bcl-W in RS4;11 B-ALL cells at 1 µM. It is cytotoxic to MOLT-4 cells but not washed isolated human platelets (EC₅₀s = 0.052 and >3 µM, respectively) and induces cleavage of caspase-3 in MOLT-4 cells when used at concentrations of 100 and 300 nM. DT2216 (15 mg/kg) reduces tumor volume and weight in a MOLT-4 mouse xenograft model. It acts synergistically with the Bcl-2 inhibitor ABT-199 (Item No. 16233) in an NCI H146 small cell lung cancer (SCLC) mouse xenograft model and the microtubule-stabilizing anticancer agent docetaxel (Item No. 11637) in an MDA-MB-231 breast cancer mouse xenograft model.

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1. Khan, S., Zhang, X., Lv, D., et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 25(12), 1938-1947 (2019).