Abstract 4619: Disabling oncogenic signaling with Apertor Interceptors - Proximity inducing bisteric molecules

Abstract All proteins including those encoded by corrupted DNA in diseased tissues, convey cellular instructions in partnership with other physically interacting proteins. Disrupting these protein-protein interactions (PPIs) to achieve therapeutic goals face a number of daunting chemistry challenges, including the shallow chemical-target interfaces to achieve selective PPI disruption typically found in cell membrane penetrant small molecules. Here we introduce bisteric molecules (AP Interceptors) that are able to traverse the cell membrane and recruit abundantly expressed members of the intracellular FKBP protein family to achieve selective disruption of PPIs essential to the function of several oncogenic driver proteins. We demonstrate the durable effects of AP Interceptors in blocking the growth of cancerous cells harboring alterations in KRAS and present a mechanistic account of their anti-cancer activity. Citation Format: Andrew Robertson, Shinji Kasahara, Jennifer Schmidt, Bo Pang, Nage Yarravarapu, Diego Garrido Ruiz, Rose Citron, Arash Samadi, Denisse Martinez, Nefeli Chanoutsi, Colleen Mulvihill, Arushi Singhai, Vinh Thai, Raissa Estrela Curado, Ericka Mendez, Edmund Graziani, Lawrence Lum, . Disabling oncogenic signaling with Apertor Interceptors - Proximity inducing bisteric molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4619.