A single dose of KT-253 induced rapid apoptosis and sustained tumor regression in xenograft models of AML

KT-253 demonstrated combinatorial utility with the BCL-2 inhibitor venetoclax in the venetoclax-resistant AML model

KT-253 is also active in other hematological malignancies, including DLBCL

WATERTOWN, Mass., December 11, 2022 (GLOBE NEWSWIRE) — Kymera Therapeutics, Inc. CYMR, a clinical-stage biopharmaceutical company advancing targeted protein degradation to provide novel small molecule protein-degrading drugs, today presented preclinical data showing that KT-253, a novel MDM2-degrading agent, as a single agent and in combination with venetoclax inhibited tumor growth in AML xenograft models. The data were presented at the American Society of Hematology (ASH) Annual Meeting, being held December 10-13, 2022 in New Orleans, Louisiana.

The mouse oncoprotein double minute 2 (MDM2) is the E3 ligase that ubiquitinates and degrades the p53 tumor suppressor. While reversible small molecule inhibitors (SMIs) of the MDM2/p53 interaction have been developed to stabilize p53 to induce cancer cell death in p53 wild-type (WT) tumors, they induce a feedback loop that upregulates the MDM2 protein and thereby the p53 protein levels reduced – limitation of their biological activity and clinical application. Recent clinical trials of MDM2 inhibitors, particularly in relapsed/refractory acute myeloid leukemia (AML), have resulted in suboptimal clinical activity, underscoring the need for new therapeutic approaches to treat WT p53 hematological and solid malignancies. Due to their catalytic mechanism, MDM2 degraders can overcome the feedback loop and result in more efficient p53 stabilization and induction of an acute apoptotic response in tumor cells.

Kymera previously shown that KT-253, a novel, highly potent and selective heterobifunctional MDM2 degradant, exhibited superior activity compared to MDM2 SMIs and showed more than 200-fold improvements in both in vitro cell growth and cell growth…