Discovery and Optimization of Novel Apo-IDO1 Inhibitors by a Pharmacophore-Based Structural Simplification Strategy

  • J Med Chem. 2025 Mar 27;68(6):6633-6655. doi: 10.1021/acs.jmedchem.5c00034.
Lifang Cen  1 ,  Yunze Wu  1 ,  Mingchao He  2 ,  Jingling Huang  1 ,  Weijie Ren  1 ,  Beibei Liu  1 ,  Liuqiong Meng  1 ,  Lei Huang  1 ,  Hongfeng Gu  1 ,  Yungen Xu  1  3 ,  Qihua Zhu  1 ,  Yi Zou  1
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 2. School of Public Health, Rutgers University, 683 Hoes Lane West, Piscataway, New Jersey 08854, United States.
  • 3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China.
PMID: 40042617 DOI: 10.1021/acs.jmedchem.5c00034
Abstract

Indoleamine 2,3-dioxygenase-1 (IDO1) plays a crucial role in tumor immune escape. However, the limited clinical efficacy of traditional IDO1 inhibitors has impeded their further development. Recently, apo-IDO1 inhibitors that displace the heme to target IDO1 have been discovered, which exhibits a slow dissociation rate reminiscent of irreversible inhibitors. This characteristic suggests sustained target engagement, offering a pharmacodynamic advantage. Therefore, the development of apo-IDO1 inhibitors emerges as a promising strategy in the field of IDO1-related studies. Here, we present the identification of the thienopyrimidine derivative XW-001 through structure-based virtual screening, followed by an iterative optimization process that led to the development of XW-032. XW-032 exhibited remarkable in vitro inhibitory activity against apo-IDO1 (IC50 = 21 ± 5 nM) through a pharmacophore-guided structural simplification approach. Notably, XW-032 (TGI = 63%) exhibited potent in vivo antitumor efficacy in the CT26 syngeneic mouse model, highlighting the benefits of apo-IDO1 inhibitors for tumor immunotherapy.

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