Structure-based design of CDC42 effector interaction inhibitors for the treatment of cancer
Sohail Jahid,
Jose A. Ortega,
Linh M. Vuong,
Isabella Maria Acquistapace,
Stephanie J. Hachey,
Jessica L. Flesher,
Maria Antonietta La Serra,
Nicoletta Brindani,
Giuseppina La Sala,
Jacopo Manigrasso,
Jose M. Arencibia,
Sine Mandrup Bertozzi,
Maria Summa,
Rosalia Bertorelli,
Andrea Armirotti,
Rongsheng Jin,
Zheng Liu,
Chi-Fen Chen,
Robert Edwards,
Christopher C.W. Hughes,
Marco De Vivo,
Anand K. Ganesan
Affiliations
Sohail Jahid
Department of Dermatology, University of California, Irvine, CA 92697, USA
Jose A. Ortega
Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
Linh M. Vuong
Department of Dermatology, University of California, Irvine, CA 92697, USA
Isabella Maria Acquistapace
Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
Stephanie J. Hachey
Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA
Jessica L. Flesher
Department of Biological Chemistry, University of California, Irvine, CA 92697, USA
Maria Antonietta La Serra
Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
Nicoletta Brindani
Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
Giuseppina La Sala
Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
Jacopo Manigrasso
Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
Jose M. Arencibia
Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
Sine Mandrup Bertozzi
Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
Maria Summa
Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
Rosalia Bertorelli
Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
Andrea Armirotti
Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
Rongsheng Jin
Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA
Zheng Liu
Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA
Chi-Fen Chen
Department of Dermatology, University of California, Irvine, CA 92697, USA
Robert Edwards
Department of Pathology and Lab Medicine, University of California, Irvine, CA 92697, USA
Christopher C.W. Hughes
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA
Marco De Vivo
Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy; Corresponding author
Anand K. Ganesan
Department of Dermatology, University of California, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, CA 92697, USA; Corresponding author
Summary: 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 chemical entity (ARN22089) that 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 3D vascularized microtumor models (VMT) in vitro. Additionally, ARN22089 has a favorable pharmacokinetic profile and can inhibit the growth of BRAF mutant mouse melanomas and patient-derived xenografts in vivo. ARN22089 selectively blocks CDC42 effector interactions without affecting the binding between closely related GTPases and their downstream effectors. Taken together, we identify a class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment.
