Author:
Jahid Sohail,Ortega Jose A.,Vuong Linh M.,Acquistapace Isabella Maria,Hachey Stephanie J.,Flesher Jessica L.,La Serra Maria Antonietta,Brindani Nicoletta,La Sala Giuseppina,Manigrasso Jacopo,Arencibia Jose M.,Bertozzi Sine Mandrup,Summa Maria,Bertorelli Rosalia,Armirotti Andrea,Jin Rongsheng,Liu Zheng,Chen Chi-Fen,Edwards Robert,Hughes Christopher C.W.,Vivo Marco De,Ganesan Anand K.
Abstract
SUMMARYCDC42 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.
Publisher
Cold Spring Harbor Laboratory