2. Academic Validation
  3. Design, synthesis and biological evaluation of 1H-pyrazolo [3,4-d]pyrimidine derivatives as PAK1 inhibitors that trigger apoptosis, ER stress and anti-migration effect in MDA-MB-231 cells

Design, synthesis and biological evaluation of 1H-pyrazolo [3,4-d]pyrimidine derivatives as PAK1 inhibitors that trigger apoptosis, ER stress and anti-migration effect in MDA-MB-231 cells

  • Eur J Med Chem. 2020 May 15;194:112220. doi: 10.1016/j.ejmech.2020.112220.
Jin Zhang 1,  Ling Zou 2,  Pan Tang 2,  Dabo Pan 3,  Zhendan He 4,  Dahong Yao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China. Electronic address: [email protected].
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
  • 3 Institute of Traditional Chinese Medicine & Natural Products, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
  • 4 School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, 518060, China.
  • 5 School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, 518060, China. Electronic address: [email protected].
PMID: 32222676 DOI: 10.1016/j.ejmech.2020.112220
Abstract

p21-Activated Kinase 1 (PAK1) is associated with cell proliferation, survival and migration. Deregulation of PAK1 activity is involved in various human diseases, including Cancer, inflammation, and neurological disorders. Using a high-throughput virtual screening, we identified the 1H-pyrazolo [3,4-d]pyrimidine scaffold as a promising lead for targeting PAK1. We designed and synthesized a focused library through a structure-based strategy. A novel potent PAK1 Inhibitor, ZMF-10, was discovered, which presented an IC50 value of 174 nM with a good selectivity. In addition, ZMF-10 could inhibit PAK1-ERK signaling to suppress MDA-MB-231 cells proliferation with an IC50 value of 3.48 μM for 48 h. Subsequently, ZMF-10 was documented to induce cell Apoptosis. Interestingly, according to the RNASeq-based analyses, we substantiated that ZMF-10 induced significant ER-Stress, suppressed migration via FOXO3 activation, JNK1/2, ERK1/2 and Akt signaling inhibition. Together, these results demonstrate that ZMF-10 is a novel PAK1 Inhibitor triggering Apoptosis, ER stress and anti-migration effect in MDA-MB-231 cells, which may provide a candidate lead for the development of novel potent inhibitors of PAK1.

Keywords

Apoptosis; Breast cancer; High-throughput screening; Migration; PAK1 inhibitor.

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