Discovery of novel pyrazolo[1,5-a]pyrimidine derivatives as selective ROCK2 inhibitors with anti-breast cancer migration and invasion activities.
Bioorg Chem
; 151: 107675, 2024 Oct.
Article
in En
| MEDLINE
| ID: mdl-39126868
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrazoles
/
Pyrimidines
/
Breast Neoplasms
/
Drug Screening Assays, Antitumor
/
Cell Movement
/
Protein Kinase Inhibitors
/
Dose-Response Relationship, Drug
/
Rho-Associated Kinases
/
Antineoplastic Agents
Limits:
Female
/
Humans
Language:
En
Journal:
Bioorg Chem
/
Bioorganic chem
/
Bioorganic chemistry
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
United States