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Structure-based design of CDC42 effector interaction inhibitors for the treatment of cancer.
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; De Vivo, Marco; Ganesan, Anand K.
Affiliation
  • Jahid S; Department of Dermatology, University of California, Irvine, CA 92697, USA.
  • Ortega JA; Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • Vuong LM; Department of Dermatology, University of California, Irvine, CA 92697, USA.
  • Acquistapace IM; Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • Hachey SJ; Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
  • Flesher JL; Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
  • La Serra MA; Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • Brindani N; Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • La Sala G; Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • Manigrasso J; Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • Arencibia JM; Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • Bertozzi SM; Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • Summa M; Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • Bertorelli R; Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • Armirotti A; Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • Jin R; Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
  • Liu Z; Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
  • Chen CF; Department of Dermatology, University of California, Irvine, CA 92697, USA.
  • Edwards R; Department of Pathology and Lab Medicine, University of California, Irvine, CA 92697, USA.
  • Hughes CCW; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
  • De Vivo M; Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy. Electronic address: marco.devivo@iit.it.
  • Ganesan AK; Department of Dermatology, University of California, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, CA 92697, USA. Electronic address: aganesan@uci.edu.
Cell Rep ; 39(1): 110641, 2022 04 05.
Article in En | MEDLINE | ID: mdl-35385746
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Endothelial Cells / Neoplasms Limits: Animals / Humans Language: En Journal: Cell Rep Year: 2022 Document type: Article Affiliation country:
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Endothelial Cells / Neoplasms Limits: Animals / Humans Language: En Journal: Cell Rep Year: 2022 Document type: Article Affiliation country: