2. Academic Validation
  3. Synthesis and biological evaluation of 7H-pyrrolo [2,3-d] pyrimidine derivatives as potential p21-activated kinase 4 (PAK4) inhibitors

Synthesis and biological evaluation of 7H-pyrrolo [2,3-d] pyrimidine derivatives as potential p21-activated kinase 4 (PAK4) inhibitors

  • Bioorg Med Chem. 2022 Apr 15;60:116700. doi: 10.1016/j.bmc.2022.116700.
Cong Wang 1,  Jiawei Xia 1,  Yan Lei 1,  Rui Lu 1,  Mingliang Zhang 1,  He Lv 1,  Qianqian Hong 1,  Tao Lu 2,  Yadong Chen 2,  Hongmei Li 3
Affiliations

Affiliations

  • 1 Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing 211198, PR China.
  • 2 Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
  • 3 Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing 211198, PR China. Electronic address: [email protected].
PMID: 35272236 DOI: 10.1016/j.bmc.2022.116700
Abstract

PAK4 has been validated as a crucial effector of various signal pathways and play an important role in driving tumor progression. Here, we developed a series of 7H-pyrrolo [2,3-d] pyrimidine derivatives as PAK4 inhibitors. Compounds 5n and 5o showed higher enzymatic inhibitory activities (IC50 = 2.7 and 20.2 nM, respectively) and potent activity (IC50 = 7.8 and 38.3 nM, respectively) against MV4-11 cell line. Further flow cytometry assay revealed that the compound 5n can arrest MV4-11 cells at G0/G1 phase and induce cell Apoptosis. Molecular mechanism study indicated that compound 5n regulated the phosphorylation of PAK4 in vitro. The docking study supported that compound 5n binds to PAK4 through various hydrogen bonding interactions and hydrophobic interactions. Thus, compound 5n represents a promising lead for the discovery of PAK4 directed therapeutic agents and may be considered for further drug development.

Keywords

7H-pyrrolo [2,3-d] pyrimidine scaffold; Anti-tumor effect; PAK4 inhibitor; p21-Activated kinase.

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