2. Academic Validation
  3. Discovery of a potent and selective JAK1-targeting PROTAC degrader with anti-tumor activities

Discovery of a potent and selective JAK1-targeting PROTAC degrader with anti-tumor activities

  • Bioorg Med Chem Lett. 2024 Sep 1:109:129838. doi: 10.1016/j.bmcl.2024.129838.
Xiaoyu Zhang 1,  Wei Wang 2,  Guoqiang Dong 2,  Yingqi Song 3,  Xin Zhai 4,  Chunquan Sheng 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 2 The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, PR China.
  • 3 School of Pharmaceutical Sciences, Hainan University, Haikou 570228, PR China.
  • 4 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: zhaixin_syphu@126.com.
  • 5 The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, PR China. Electronic address: shengcq@smmu.edu.cn.
PMID: 38838918 DOI: 10.1016/j.bmcl.2024.129838
Abstract

Aberrant activation of the JAK-STAT pathway is evident in various human diseases including cancers. Proteolysis targeting chimeras (PROTACs) provide an attractive strategy for developing novel JAK-targeting drugs. Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor-momelotinib as the warhead. The most promising compound 10c exhibited both good enzymatic potency and cellular antiproliferative effects. Western blot analysis revealed that compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner (DC50 = 214 nM). Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery.

Keywords

Antitumor drug discovery; JAK-STAT pathway; JAK1; Momelotinib; PROTAC.

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