Discovery of novel pyrazolo[1,5-a]pyrimidine derivatives as selective ROCK2 inhibitors with anti-breast cancer migration and invasion activities

Bioorg Chem. 2024 Oct:151:107675. doi: 10.1016/j.bioorg.2024.107675. Epub 2024 Aug 2.

Abstract

Rho-associated coiled-coil kinase (ROCK) is involved in multiple cellular activities regulating the actin cytoskeleton, such as cell morphology, adhesion, and migration. The inhibition of ROCK is a feasible strategy to suppress breast cancer metastasis. Herein, based on Belumosudil, a series of pyrazolo[1,5-a]pyrimidine derivatives as selective ROCK2 inhibitors were designed and synthesized. Through systematic investigation of SARs, the piperazine analog 7u was identified with optimum ROCK2 inhibitory activity (IC50 = 36.8 nM) and excellent selectivity over the isoform protein ROCK1 (>250-fold). Intriguingly, upon treatment with 7u, the arrangement of the MDA-MB-231 cytoskeleton was affected accompanied by the alteration of morphology. Furthermore, cell scratch and transwell assays indicated that 7u inhibited MDA-MB-231 cell migration and invasion in a dose-dependent manner. Ultimately, the binding model of 7u with ROCK2 well accounted for the superior activities of 7u as a promising ROCK2 inhibitor with the potential application in breast cancer metastasis treatment.

Keywords: Breast cancer metastasis; Inhibitors; Pyrazolo[1,5-a]pyrimidine; ROCK2; Synthesis.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / pathology
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug*
  • Drug Discovery
  • Drug Screening Assays, Antitumor*
  • Female
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Pyrazoles* / chemical synthesis
  • Pyrazoles* / chemistry
  • Pyrazoles* / pharmacology
  • Pyrimidines* / chemical synthesis
  • Pyrimidines* / chemistry
  • Pyrimidines* / pharmacology
  • Structure-Activity Relationship
  • rho-Associated Kinases* / antagonists & inhibitors
  • rho-Associated Kinases* / metabolism

Substances

  • rho-Associated Kinases
  • ROCK2 protein, human
  • Pyrimidines
  • Protein Kinase Inhibitors
  • Antineoplastic Agents
  • Pyrazoles
  • pyrazolo(1,5-a)pyrimidine