Kymera Therapeutics announces presentation at AACR annual meeting

Kymera Therapeutics announced that new preclinical data showing the structural and molecular mechanisms underlying anti-tumor activity of its novel STAT3 degrader, KT-333, were presented in a late-breaking research poster session at the AACR Annual Meeting taking place April 5-10, 2024, in San Diego, California. Additionally, Nello Mainolfi, PhD, Founder, President and CEO, will present in the Major Symposium at the conference highlighting the Company’s unique target selection strategy and strong preclinical to clinical translation observed across the Company’s first-in-class oncology programs, KT-333 and KT-253, a potent and selective degrader of MDM2. “Guided by our drug development principles and innovative platform capabilities and know-how, we have designed highly potent and selective degraders against undrugged and poorly drugged targets, including oncogenic proteins in key signaling pathways, that have disruptive therapeutic potential,” said Dr. Mainolfi. “Our precise understanding of E3 ligase pairing, ternary complex molecular mechanisms at the atomic level, and accuracy of PK and PD, as presented at AACR, has resulted in impeccable translation of our pipeline in the clinic and continues to validate our differentiated molecular design, target selection, and translational strategies to advance a new generation of medicines for patients.” STAT3 is recognized as a key component of the JAK-STAT signaling pathway with both tumor cell intrinsic and tumor cell extrinsic effects on the tumor microenvironment. Although multiple drugs have been approved that target upstream effectors signaling through STAT3, no known drugs selectively block STAT3 broadly across all relevant cell types or address both phosphorylation-dependent and -independent functions of STAT3. For these reasons, STAT3 degraders may provide a solution to the development of targeted and selective drugs to address multiple STAT3 dependent pathologies. New findings presented for the first time show KT-333 induces a strong ternary complex between STAT3 and the VHL E3 ligase in a positively cooperative manner, exhibiting properties of native protein complexes, leading to potent, selective, rapid, and consistent degradation as observed in vitro and in vivo. Innovative structure-based design with cryo-electron microscopy, biochemical, and proteomics techniques provide mechanistic and structural insights further validating VHL as the E3 ligase of choice for STAT3 degradation in cancer. In the STAT3-dependent SUDHL-1 lymphoma xenograft model, reduced expression of canonical STAT3 targets and down-regulation of cytokine-mediated signaling and cell cycle signature genes indicated that cell cycle arrest and subsequent apoptosis were the main drivers of efficacy for KT-333. Additionally, this unique mechanism of action led to induction of proinflammatory anti-tumorigenic transcriptional signatures in the tumor microenvironment. This has resulted in robust antitumor activity in patients, as reported in the Company’s latest clinical update at the American Society of Hematology Annual Meeting in December 2023.