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Kymera Therapeutics Presents Preclinical Data Demonstrating Activity of KT-253, a Selective Heterobifunctional MDM2 Degrader, in Acute Myeloid Leukemia at the American Society of Hematology Annual Meeting
A single dose of KT-253 induced rapid apoptosis and sustained tumor regression in xenograft models of AML KT-253 showed combinatorial benefit with BCL-2
About this update from Kymera Therapeutics, Inc.
[{"type":"text","content":"A single dose of KT-253 induced rapid apoptosis and sustained tumor regression in xenograft models of AML KT-253 showed combinatorial benefit with BCL-2 inhibitor venetoclax in model of venetoclax-resistant AML KT-253 also active in other hematologic malignancies including DLBCL WATERTOWN, Mass., Dec. 11, 2022 (GLOBE NEWSWIRE) -- Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage biopharmaceutical company advancing targeted protein degradation to deliver novel small molecule protein degrader medicines, today presented preclinical data showing that KT-253, a novel MDM2 degrader, inhibited tumor growth as single agent and in combination with venetoclax in AML xenograft models. The data was presented at the American Society of Hematology (ASH) Annual Meeting, taking place from December 10 - 13, 2022 in New Orleans, Louisiana. The murine double minute 2 (MDM2) oncoprotein 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 in order to induce cancer cell death in wildtype (WT) p53 tumors, they induce a feedback loop that upregulates MDM2 protein and thereby reduces p53 protein levels – limiting their biological activity and clinical application. Recent clinical trials with MDM2 inhibitors, especially in relapsed/refractory Acute Myeloid Leukemia (AML), have resulted in suboptimal clinical activity, highlighting the need for novel therapeutic approaches to treat WT p53 hematologic and solid tumor malignancies. MDM2 degraders, because of their catalytic mechanism, can overcome the feedback loop and lead to more efficient p53 stabilization and induction of an acute apoptotic response in tumor cells. Kymera previously showed that KT-253, a novel, highly potent and selective heterobifunctional MDM2 degrader, has superior activity compared to MDM2 SMIs and demonstrated greater than 200-fold improvements in both in vitro cell growth inhibition and apoptosis. Because of the distinct pharmacological profile compared to MDM2/p53 SMIs, a single dose of KT-253 was sufficient to induce rapid apoptosis and sustained tumor regression in the MV4;11 AML and RS4;11 ALL cell line-derived (CDX) mouse xenograft models. New results in AML now demonstrate that KT-253 administered once every three weeks led to tu...