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Characterization of Anticancer Effects of the Analogs of DJ4, a Novel Selective Inhibitor of ROCK and MRCK Kinases

Vijay Pralhad Kale1, Jeremy A Hengst1, Arati K Sharma1

  • 1Department of Pharmacology Penn State College of Medicine, Hershey, PA 17033, USA.

Pharmaceuticals (Basel, Switzerland)
|August 26, 2023
PubMed

Insights

Novel small molecules targeting ROCK/MRCK kinases show promise in inhibiting cancer cell proliferation and migration. Dual inhibitors were more effective at inducing cell death than ROCK/MRCK selective inhibitors.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Rho-associated coiled-coil containing protein kinases (ROCK1/2) and myotonic dystrophy-related Cdc-42 binding kinases (MRCKα/β) are key regulators of cell proliferation, plasticity, migration, and invasion.
  • Dysregulation of these kinases is implicated in cancer progression.
  • A previously discovered selective multi-kinase inhibitor, DJ4, targets ROCK1/2 and MRCKα/β.

Purpose of the Study:

  • To characterize the anti-proliferative and apoptotic effects of DJ4 in non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC) cells.
  • To optimize DJ4's ROCK/MRCK inhibitory potency by generating and evaluating analogs.
  • To assess the anti-cancer efficacy of DJ4 and its analogs across various cancer types and their anti-migratory effects.

Main Methods:

  • Synthesis and screening of 27 DJ4 analogs for ROCK/MRCK inhibitory activity.
  • Evaluation of anti-proliferative and cell cycle inhibitory effects in NSCLC, breast cancer, and melanoma cell lines.
  • Assessment of anti-proliferative activity using the NCI-60 human cancer cell line panel.
  • Testing of anti-migratory effects in MDA-MB-231 breast cancer cells.

Main Results:

  • Four active analogs with enhanced ROCK/MRCK inhibitory potency were identified.
  • DJ4 and active analogs demonstrated anti-proliferative and cell cycle inhibitory effects in multiple cancer cell lines.
  • DJ4 and DJ110 (dual ROCK/MRCK inhibitors) were more effective in inducing cell death than selective ROCK1/2 inhibitors (DJE4, DJ-Allyl).
  • Selective ROCK1/2 inhibitors induced G2/M cell cycle arrest but showed limited cell death induction.

Conclusions:

  • DJ4 and its analogs are potent inhibitors of ROCK/MRCK kinases with significant anti-proliferative and anti-migratory effects.
  • Dual ROCK/MRCK inhibition is more effective in inducing cancer cell death compared to selective ROCK1/2 inhibition.
  • These findings highlight the therapeutic potential of ROCK/MRCK inhibitors in cancer treatment, particularly dual inhibitors.
Keywords:
MRCKROCKcancerinvasionmetastasismulti-kinase inhibitor

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