KTX-049 / Kymera Therap - LARVOL DELTA

Targeted degradation of MDM2 overcomes feedback regulation of p53 signaling in Merkel cell carcinoma models. (PubMed, J Clin Invest) - "We demonstrate that MDM2 degraders KTX-049 and KT-253 overcome this limitation by collapsing the p53/MDM2 negative feedback loop. KTX-049 was >100-fold more potent than the MDM2 inhibitor DS-3032 across WT p53 MCC cell lines, and this superior potency was quantitatively supported by mechanistic mathematical modeling...Acquired resistance was strongly associated with acquisition of TP53 mutations, confirming on-target pathway pressure. These findings establish feedback architecture as a critical determinant of therapeutic response and position MDM2 degradation as a qualitatively distinct strategy that produces more durable pathway engagement than MDM2 inhibition, providing a preclinical rationale for prioritizing MDM2 degraders in WT TP53 MCC."

Journal • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • MYCL

The MDM2 degraders KTX-049 and KT-253 are highly active in wild-type TP53 (WT p53) Merkel cell carcinoma (MCC) (EORTC-NCI-AACR 2024) - "Here, we analyze the in vitro and in vivo efficacy of MDM2 degraders in MCC tumor models and compare their efficacy to an MDM2 small molecule inhibitor, DS-3032.Materials and Established MCCP cell lines with WT or mutant (MUT) p53 and two MCCP patient derived cell lines (PDCLs) with WT p53 were treated with KTX-049, a tool MDM2 degrader, or DS-3032. Selective and potent MDM2 degraders including clinical stage KT-253 show promising efficacy in WT p53 MCC preclinical models. These results support exploration of KT-253 clinical activity in WT p53 MCC where degradation of MDM2 is one of the key mechanisms for impeding tumor growth."

Tumor mutational burden • Endocrine Cancer • Merkel Cell Carcinoma • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • ANXA5 • CASP3 • CASP7 • EP400 • MYCL • TMB • TP53

Kymera Therapeutics Presents Preclinical Data Demonstrating Activity of MDM2 Degraders in Acute Myeloid Leukemia and Merkel Cell Carcinoma (GlobeNewswire) - "Kymera Therapeutics, Inc...reported preclinical data highlighting the therapeutic potential in liquid and solid tumors of potent and selective heterobifunctional degraders of MDM2, including KT-253. The data was presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on October 11-15, 2023, in Boston, Massachusetts and will also be shared at the 10th International MDM2 Workshop taking place October 15-18, 2023, in Tokyo, Japan....These data demonstrate in vitro efficacy of an MDM2 degrader, KTX-049, against p53 wild-type MCC cell lines that was achieved with brief compound exposure. In two MCC PDX models, KT-253 (referred to as KTX-169 in the presentation) demonstrated tumor regressions with weekly as well as every three-week dosing whereas an MDM2 SMI only showed modest tumor growth inhibition."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor