TY - JOUR T1 - Structure-based Design of CDC42 Effector Interaction Inhibitors For the Treatment of Cancer JF - bioRxiv DO - 10.1101/2021.10.14.464305 SP - 2021.10.14.464305 AU - Sohail Jahid AU - Jose A. Ortega AU - Linh M. Vuong AU - Isabella Maria Acquistapace AU - Stephanie J. Hachey AU - Jessica L. Flesher AU - Maria Antonietta La Serra AU - Nicoletta Brindani AU - Giuseppina La Sala AU - Jacopo Manigrasso AU - Jose M. Arencibia AU - Sine Mandrup Bertozzi AU - Maria Summa AU - Rosalia Bertorelli AU - Andrea Armirotti AU - Rongsheng Jin AU - Zheng Liu AU - Chi-Fen Chen AU - Robert Edwards AU - Christopher C.W. Hughes AU - Marco De Vivo AU - Anand K. Ganesan Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/10/14/2021.10.14.464305.abstract N2 - CDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. Here we use computer-aided drug design to discover a new chemical entity (ARN22089) that targets CDC42 GTPases and blocks CDC42 effector interactions without affecting the binding between closely related GTPases (RAC1, RAS, RAL) and their downstream effectors. Our lead compound has broad activity against a panel of cancer cell lines, inhibits S6 phosphorylation and MAPK activation, activates pro-inflammatory and apoptotic signaling, and blocks tumor growth and angiogenesis in three-dimensional vascularized microtumor models (VMT) in vitro. In addition, ARN22089 has a favorable pharmacokinetic profile and can inhibit the growth of BRAF mutant mouse melanomas and patient-derived xenografts in vivo. Taken together, this work identifies a promising new class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment.Competing Interest StatementAnand Ganesan and Marco De Vivo are co-founders of a company entitled Alyra Therapeutics based on the technology presented in this manuscript. ER -