2. Academic Validation
  3. Discovery of CDC42 Inhibitors with a Favorable Pharmacokinetic Profile and Anticancer In Vivo Efficacy

Discovery of CDC42 Inhibitors with a Favorable Pharmacokinetic Profile and Anticancer In Vivo Efficacy

  • J Med Chem. 2024 Jun 27;67(12):10401-10424. doi: 10.1021/acs.jmedchem.4c00855.
Nicoletta Brindani 1,  Linh M Vuong 2,  Maria Antonietta La Serra 1,  Noel Salvador 2,  Andrea Menichetti 1,  Isabella Maria Acquistapace 1,  Jose Antonio Ortega 1,  Marina Veronesi 3,  Sine Mandrup Bertozzi 4,  Maria Summa 5,  Stefania Girotto 3,  Rosalia Bertorelli 5,  Andrea Armirotti 4,  Anand K Ganesan 2,  Marco De Vivo 1
Affiliations

Affiliations

  • 1 Molecular Modeling and Drug Discovery Lab, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
  • 2 Department of Dermatology, University of California, Irvine, California 92697, United States.
  • 3 Structural Biophysics Facility, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
  • 4 Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
  • 5 Translational Pharmacology Facility, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
PMID: 38866385 DOI: 10.1021/acs.jmedchem.4c00855
Abstract

We previously reported trisubstituted pyrimidine lead compounds, namely, ARN22089 and ARN25062, which block the interaction between CDC42 with its specific downstream effector, a PAK protein. This interaction is crucial for the progression of multiple tumor types. Such inhibitors showed Anticancer efficacy in vivo. Here, we describe a second class of CDC42 inhibitors with favorable drug-like properties. Out of the 25 compounds here reported, compound 15 (ARN25499) stands out as the best lead compound with an improved pharmacokinetic profile, increased bioavailability, and efficacy in an in vivo PDX tumor mouse model. Our results indicate that these CDC42 inhibitors represent a promising chemical class toward the discovery of Anticancer drugs, with ARN25499 as an additional lead candidate for preclinical development.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161736
    CDC42 Inhibitor
    CDK