2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Selective PAK4 Degrader for the Treatment of Lung Tumor Metastasis

Design, Synthesis, and Biological Evaluation of Selective PAK4 Degrader for the Treatment of Lung Tumor Metastasis

  • J Med Chem. 2025 Jun 12;68(11):11231-11269. doi: 10.1021/acs.jmedchem.5c00197.
Hanxun Wang 1 2,  Peilu Song 1 3,  Yujie Wang 1,  Hanqing Xu 4,  Lanlan Shen 1,  Zhuo Qi 1,  Lu Chen 1,  Lanyan Ma 1,  Zhijian Wang 1,  Xingqi Hu 1,  Wanqing Wang 1,  Na Li 1,  Yage Yu 1,  Yinli Gao 1,  Mingyu Xia 5,  Dongmei Zhao 1,  Jian Wang 1,  Maosheng Cheng 1
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 2 School of Traditional Chinese Materia Medica, Key Laboratory of Innovative Traditional Chinese Medicine for Major Chronic Diseases of Liaoning Province, Key Laboratory for TCM Material Basis Study and Innovative Drug Development of Shenyang City, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 3 School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 100098, People's Republic of China.
  • 4 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 5 School of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
PMID: 40404481 DOI: 10.1021/acs.jmedchem.5c00197
Abstract

PAK4, the most studied member of group II PAK, plays crucial roles in multiple Cancer cell signaling pathways. To date , only PAK4 Inhibitor KPT9274 is under clinical development with no detailed binding mechanism. The PROTAC technology offers a new chance to study PAK4 by selective protein degradation. Here, we report the development of CPS-021, a selective PAK4 degrader derived from our previously reported compound CPL-042 conjugated to pomalidomide. CPS-021 induced selective degradation of PAK4 with DC50 = 50 nM and exhibited significant antimigratory and invasive activity. The A549-luc lung metastasis in vivo model demonstrated that CPS-021 effectively inhibited the invasion and metastasis of tumor cells in nude mice. Our findings provide evidence that the selective PAK4 degrader exhibits significant pharmacological effects in suppressing Cancer cell migration and invasion. These results support the further development of CPS-021 as a valuable tool compound for conducting in-depth biological investigations of group II PAKs.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-174248
    Negative Control