2. Academic Validation
  3. Re-Evaluating PIN1 as a Therapeutic Target in Oncology Using Neutral Inhibitors and PROTACs

Re-Evaluating PIN1 as a Therapeutic Target in Oncology Using Neutral Inhibitors and PROTACs

  • J Med Chem. 2024 Sep 12;67(17):15780-15795. doi: 10.1021/acs.jmedchem.4c01412.
Chuan Liu 1,  Zhonghui Chen 2,  Tao Chen 1,  Hongmei Song 2,  Jianbo Shen 1,  Xiaoxi Yuan 2,  Shuai Xia 1,  Qian Liu 2,  Qiuxia Chen 1,  Qiang Tian 2,  Xiaoyun Meng 1,  Zhu Han 2,  Xiaofei Dong 1,  Yu Yang 2,  Longying Cai 1,  Xuemin Cheng 1,  Yangyang Jia 2,  Guansai Liu 1,  Jin Li 1,  Junyou Ge 2,  Dengfeng Dou 1
Affiliations

Affiliations

  • 1 HitGen Inc., Shuangliu District, Chengdu, Sichuan 610200, P. R. China.
  • 2 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd., Wenjiang District, Chengdu, Sichuan 611138, P. R. China.
PMID: 39229909 DOI: 10.1021/acs.jmedchem.4c01412
Abstract

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) has emerged as a promising therapeutic target for Cancer treatment. However, the current PIN1 inhibitors have shown limited efficacy in animal models, leaving the question of whether PIN1 is a proper oncologic target still unanswered. By screening a 1 trillion DNA-encoded library (DEL), we identified novel nonacidic compounds. Among resynthesized DEL compounds, DEL1067-56-469 (A0) is the most potent one (KD = 430 nM, IC50 = 420 nM). Further optimization of A0 resulted in compound C10 with much improved potency (KD = 25 nM, IC50 = 150 nM). As an alternative approach, C10 was then converted into proteolysis targeting chimeras (PROTACs) in order to achieve deeper downregulation of the PIN1 protein in Cancer cell lines. Unfortunately, neither PIN1 inhibitors nor PIN1 PROTACs demonstrated meaningful antiproliferation activity. In addition, siRNA knock-down experiments provided unfavorable evidence of PIN1 as an oncologic target. Our findings highlight the complexity of targeting PIN1 for Cancer therapy.

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