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Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
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Identification and Biological Evaluation of a Novel CLK4 Inhibitor Targeting Alternative Splicing in Pancreatic

Chun-Lin Yang1, Yi-Wen Wu1, Huang-Ju Tu1

  • 1Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 110301, Taiwan.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|March 24, 2025
PubMed
Summary

A novel compound, 150441, effectively inhibits CDC-like kinase 4 (CLK4) and suppresses pancreatic cancer cell growth. This CLK4 inhibitor shows promise for developing new pancreatic cancer treatments by targeting aberrant splicing.

Keywords:
CLK4alternative splicingkinase inhibitorpancreatic cancerstructure‐based virtual screening

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Pancreatic cancer is an aggressive malignancy with limited treatment options.
  • Aberrant alternative splicing, regulated by CDC-like kinase 4 (CLK4), drives pancreatic cancer progression.

Purpose of the Study:

  • To develop a computational model for identifying CLK4 inhibitors.
  • To identify and characterize a novel CLK4 inhibitor for pancreatic cancer treatment.

Main Methods:

  • Established a computational model for CLK4 inhibitor screening.
  • Identified compound 150441 and performed structure-activity relationship analysis.
  • Conducted in vitro assays, kinase profiling, cell cycle analysis, and RNA-seq analysis.

Main Results:

  • Compound 150441 demonstrated potent and selective inhibition of CLK4 (IC50 = 21.4 nM).
  • The inhibitor suppressed pancreatic cancer cell growth, viability, and phosphorylation of splicing factors (SRSF4, SRSF6).
  • Compound 150441 induced G2/M cell cycle arrest, apoptosis, and significant alterations in alternative splicing and key biological pathways.

Conclusions:

  • Compound 150441 is a novel, selective CLK4 inhibitor with significant anti-pancreatic cancer activity.
  • The compound's ability to modulate alternative splicing and induce apoptosis suggests therapeutic potential.
  • Compound 150441 warrants further investigation for pancreatic cancer treatment development.