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Updated: Jul 8, 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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The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma

Thibault Houles1, Jonathan Boucher2, Geneviève Lavoie2

  • 1Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada. thibault.houles@igmm.cnrs.fr.

Cell Death Discovery
|December 16, 2023
PubMed

Insights

The CDK12 inhibitor SR-4835 uniquely targets cyclin K for proteasomal degradation by acting as a molecular glue. This action recruits the CDK12-cyclin K complex to a ubiquitin ligase, offering new therapeutic strategies for cancers like breast cancer and melanoma.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cancer Biology

Background:

  • CDK12 (cyclin-dependent kinase 12) is a transcriptional kinase regulating gene expression via phosphorylation of RNA polymerase II.
  • Dysregulation of CDK12 is implicated in various cancers, including breast cancer and melanoma, leading to the development of inhibitors like THZ531 and SR-4835.
  • While both inhibitors affect Pol II phosphorylation, SR-4835 exhibits a unique mechanism involving cyclin K degradation.

Purpose of the Study:

  • To elucidate the distinct mechanism of action of the CDK12 inhibitor SR-4835.
  • To investigate the role of the CUL4-RBX1-DDB1 ubiquitin ligase complex in SR-4835's effects.
  • To characterize SR-4835's molecular glue activity.

Main Methods:

  • Loss-of-function genetic screening to identify SR-4835's dependencies.
  • Biochemical assays to assess protein interactions and degradation.
  • Docking studies and structure-activity relationship (SAR) analyses.

Main Results:

  • SR-4835 uniquely induces cyclin K degradation through the proteasome.
  • SR-4835's cytotoxicity is dependent on a functional CUL4-RBX1-DDB1 ubiquitin ligase complex.
  • SR-4835 acts as a molecular glue, promoting the interaction between the CDK12-cyclin K complex and the DDB1-containing ubiquitin ligase.
  • SAR analysis identified the benzimidazole side-chain as crucial for its molecular glue activity.

Conclusions:

  • SR-4835 functions as a molecular glue, mediating the degradation of cyclin K via the CUL4-RBX1-DDB1 ubiquitin ligase complex.
  • This novel mechanism of action provides a new avenue for therapeutic intervention in CDK12-related cancers.
  • Understanding SR-4835's mechanism can inform the design of future targeted cancer therapies.

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