Related Experiment Video

Updated: Oct 4, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

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Discovery and Optimization of Highly Selective Inhibitors of CDK5

Matthew H Daniels1, Goran Malojcic1, Susan L Clugston1

  • 1Goldfinch Bio, 215 First Street, Cambridge, Massachusetts 02142, United States.

Journal of Medicinal Chemistry
|February 10, 2022
PubMed

Insights

Researchers discovered novel, selective cyclin-dependent kinase 5 (CDK5) inhibitors, like GFB-12811, for treating autosomal dominant polycystic kidney disease (ADPKD). These compounds show promise for targeting CDK5 without affecting other kinases, offering a new therapeutic avenue.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Genetics

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic disorder characterized by kidney cyst formation.
  • Current therapeutic options for ADPKD are limited, with only tolvaptan approved for treating kidney cysts.
  • Cyclin-dependent kinase 5 (CDK5) has emerged as a potential therapeutic target for ADPKD.

Purpose of the Study:

  • To discover and characterize novel small molecules that selectively inhibit CDK5.
  • To evaluate the efficacy and selectivity of these inhibitors in cellular and in vivo models.
  • To develop tool compounds for further research into CDK5's role in ADPKD and other diseases.

Main Methods:

  • High-throughput screening and medicinal chemistry efforts to identify CDK5 inhibitors.
  • Biochemical assays to assess kinase inhibition and selectivity.
  • Cellular assays to evaluate target engagement and anti-proliferative effects.
  • In vivo pharmacokinetic studies in animal models.

Main Results:

  • Discovery of potent and highly selective CDK5 inhibitors, including GFB-12811, which spare other tested kinases.
  • Demonstrated CDK5 target engagement in cellular assays without causing anti-proliferative effects.
  • Promising in vivo pharmacokinetic profiles suitable for further preclinical development.

Conclusions:

  • The identified compounds represent a promising new class of selective CDK5 inhibitors.
  • These inhibitors can serve as valuable tool compounds for studying CDK5 function in ADPKD.
  • Further investigation of these compounds may lead to novel therapeutic strategies for ADPKD and related conditions.

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