Structure-based design of CDC42 effector interaction inhibitors for the treatment of cancer

Cell Rep. 2022 Apr 5;39(1):110641. doi: 10.1016/j.celrep.2022.110641.

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.

Keywords: CDC42/RHOJ GTPase; CP: Molecular biology; angiogenesis; cancer; inhibitor; melanoma; tumor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endothelial Cells* / metabolism
  • Humans
  • Mice
  • Neoplasms* / drug therapy
  • Neovascularization, Pathologic
  • Signal Transduction
  • Tumor Microenvironment
  • cdc42 GTP-Binding Protein / metabolism
  • rho GTP-Binding Proteins / metabolism

Substances

  • RHOJ protein, human
  • cdc42 GTP-Binding Protein
  • rho GTP-Binding Proteins