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CDKL3 is a targetable regulator of cell cycle progression in cancers

Haijiao Zhang1, Jiahui Lin1, Shaoqin Zheng1

  • 1College of Life and Health Sciences, Northeastern University, Shenyang, China.

The Journal of Clinical Investigation
|July 4, 2024
PubMed

Insights

Cyclin-dependent kinase-like 3 (CDKL3) drives cancer growth by regulating the cell cycle. A new inhibitor, HZ1, shows promise in treating various cancers, including colon cancer, by targeting CDKL3.

Area of Science:

  • Molecular oncology
  • Cell cycle regulation
  • Drug discovery

Background:

  • Aberrant cell cycle regulation is a hallmark of cancer.
  • Targeting cell cycle pathways is crucial for effective cancer therapy.
  • The role of cyclin-dependent kinase-like 3 (CDKL3) in cancer remains under-explored.

Purpose of the Study:

  • To elucidate the role of CDKL3 in cancer cell cycle progression.
  • To identify CDKL3 as a potential therapeutic target.
  • To develop and evaluate a novel CDKL3-specific inhibitor.

Main Methods:

  • In vitro and in vivo functional assays to assess CDKL3's role.
  • Biochemical studies to determine CDKL3's mechanism of action.
  • Synthesis and characterization of a CDKL3 inhibitor (HZ1).
  • Preclinical evaluation of HZ1 in pan-cancer and colon cancer models.

Main Results:

  • CDKL3 promotes cell cycle progression and growth by phosphorylating Rb and stabilizing CDK4.
  • CDKL3 inhibition leads to cell cycle arrest and suppresses tumor growth.
  • HZ1 demonstrates superior potency compared to CDK4/6 inhibitors and overcomes resistance.
  • CDKL3 is clinically relevant in colon cancer, with HZ1 showing efficacy in relevant models.

Conclusions:

  • CDKL3 is a critical driver of cancer cell cycle progression and growth.
  • Targeting CDKL3 with inhibitors like HZ1 represents a promising therapeutic strategy.
  • HZ1 offers a potential new treatment option for various cancers, including those resistant to existing therapies.
Keywords:
CancerCell biologyCell cycleDrug therapyTherapeutics

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