2. Academic Validation
  3. PB-10, a thiazolo[4,5-d] pyrimidine derivative, targets p21-activated kinase 4 in human colorectal cancer cells

PB-10, a thiazolo[4,5-d] pyrimidine derivative, targets p21-activated kinase 4 in human colorectal cancer cells

  • Bioorg Med Chem Lett. 2020 Jan 15;30(2):126807. doi: 10.1016/j.bmcl.2019.126807.
Ruijuan Li 1,  Hanxun Wang 2,  Jian Wang 3,  Maosheng Cheng 4
Affiliations

Affiliations

  • 1 College of Pharmacy, Inner Mongolia Medical University, Huhhot 010110, PR China; Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 2 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 3 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: jianwang@syphu.edu.cn.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: mscheng@syphu.edu.cn.
PMID: 31740249 DOI: 10.1016/j.bmcl.2019.126807
Abstract

Targeting p21-activated kinase 4 (PAK4) is a potential therapeutic strategy against human colorectal Cancer (CRC). In this study, we synthesized a series of novel thiazolo[4,5-d]pyrimidine derivatives (PB-1-12) and identified PB-10 (PAK4 IC50 = 15.12 μM) as a potential and potent PAK4 Inhibitor. Our results showed that PB-10 significantly suppressed the proliferation and colony formation of human CRC cells. PB-10 also arrested HCT-116 CRC cells at sub G0/G1 phase while promoting the expression of proapoptotic proteins. In addition, PB-10 inhibited migration, invasion, and adhesion as well as the PAK4 downstream signaling pathway in HCT-116 cells. Molecular docking analysis showed possible binding modes between PB-10 and PAK4. Our study provides a novel compound that may block the PAK4 signaling in CRC cells.

Keywords

Colorectal cancer; Inhibitor; Thiazolo[4,5-d]pyrimidine; p21-Activated kinase 4.

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