Targeted Bcl-XL degrader identified to treat ALL, TNBC and SCLC

INDICATION: Acute lymphoblastic leukemia (ALL); breast cancer; small cell lung cancer

A University of Florida team led by Dialectic Therapeutics Inc. co-founders Guangrong Zheng and Daohong Zhou showed the company’s lead candidate, the anti-Bcl-XL targeted protein degrader DT2216, could treat T cell ALL, triple-negative breast cancer (TNBC) and small cell lung cancer (SCLC). DT2216, which comprises the target-binding moiety of the Bcl-XL and BCL-2 dual inhibitor navitoclax linked to a vHL ligand, induced Bcl-XL degradation and death of human T cell ALL cells with EC₅₀ values of 63 nM and 52 nM, respectively. In mice with T cell ALL xenografts, DT2216 inhibited tumor growth with only transient platelet count reductions, an adverse event associated with Bcl-XL inhibition. In xenograft mouse models of TNBC and SLCL, DT2216 plus docetaxel or BCL-2 inhibitor Venclyxto venetoclax led to greater reductions in tumor growth than any of the agents as monotherapy. In a patient-derived xenograft (PDX) mouse model of T-cell ALL, combining the degrader with a chemotherapy regimen containing vincristine, dexamethasone and asparaginase led to a median survival of 72 days, up from 55 days with DT2216 and 47 days with the chemotherapy regimen alone. Dialectic plans to start clinical testing of DT2216 for liquid and solid tumors in 2021...