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.
Zhi Cao  1 ,  Xiujian Wei  1 ,  Shuming Xing  1 ,  Jiahao Zhang  1 ,  Shuqi Wang  1 ,  Lingfeng Yue  1 ,  Jiahe Zhang  1 ,  Nan Jiang  2 ,  Xin Zhai  3
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
  • 3. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
PMID: 39126868 DOI: 10.1016/j.bioorg.2024.107675
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.
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