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A Murine Cell Line Based Model of Chronic CDK9 Inhibition to Study Widespread Non-Genetic Transcriptional Elongation Defects TEdeff in Cancers
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A Murine Cell Line Based Model of Chronic CDK9 Inhibition to Study Widespread Non-Genetic Transcriptional Elongation Defects TEdeff in Cancers

Published on: September 26, 2019

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Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in

Jiacheng Li1,2, Ting Liu3, Yuanli Song2,4

  • 1The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Journal of Medicinal Chemistry
|August 4, 2022
PubMed

Insights

A novel hydrophobic tagging approach developed a small-molecule degrader, LL-K9-3, to target the CDK9-cyclin T1 complex. This degrader effectively reduced oncogene expression and showed enhanced anti-cancer effects compared to existing inhibitors.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Discovery

Background:

  • Aberrant cyclin hyperactivation drives cancer development and treatment resistance.
  • Targeted degradation of cyclin-dependent kinase (CDK)-cyclin complexes is challenging.
  • CDK9-cyclin T1 is crucial for oncogene transcription in cancers.

Purpose of the Study:

  • To develop a novel small-molecule degrader targeting the CDK9-cyclin T1 heterodimer.
  • To investigate the efficacy of the degrader in reducing oncogene expression and inhibiting cancer cell proliferation.
  • To compare the degrader's effectiveness against existing CDK9 inhibitors.

Main Methods:

  • Application of hydrophobic tagging to create a small-molecule degrader (LL-K9-3).
  • Quantitative and time-resolved proteome profiling to assess target degradation.
  • Cell-based assays in 22RV1 cells to evaluate effects on gene expression and cell viability.

Main Results:

  • LL-K9-3 selectively and synchronously degraded CDK9 and cyclin T1.
  • LL-K9-3 reduced androgen receptor (AR) and c-Myc expression.
  • LL-K9-3 demonstrated superior anti-proliferative and pro-apoptotic effects compared to SNS032 and Thal-SNS032, inhibiting downstream signaling and oncogenic transcriptional programs.

Conclusions:

  • Hydrophobic tagging is a viable strategy for developing targeted protein degraders.
  • LL-K9-3 is a potent degrader of CDK9-cyclin T1, showing significant anti-cancer activity.
  • LL-K9-3 offers a promising therapeutic approach for cancers driven by CDK9-cyclin T1 and AR/Myc signaling.

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