Discovery of Dual A2A/A2B Adenosine Receptor Antagonist and Clinical Candidate INCB106385

  • J Med Chem. 2026 Jun 11;69(11):13899-13918. doi: 10.1021/acs.jmedchem.6c00964.
Chao Qi  1 ,  Matthew S McCammant  1 ,  Yong Li  1 ,  Wenyu Zhu  1 ,  Zhiyong Yu  1 ,  Peter Carlsen  1 ,  Heeoon Han  1 ,  Le Zhao  1 ,  Fenglei Zhang  1 ,  Taisheng Huang  1 ,  Pei Gan  1 ,  Dingquan Qian  1 ,  Gia Hoang  1 ,  Chunhong He  1 ,  Song Mei  1 ,  Jennifer J Harris  1 ,  Alexandra Gallion  1 ,  Michael Hansbury  1 ,  Jennifer Mason  1 ,  Kristine Stump  1 ,  Kerri Kurzeja-Lipinski  1 ,  Angela DiRamio  1 ,  Maryanne Covington  1 ,  Holly Koblish  1 ,  Sharon Diamond  1 ,  Hui Wang  1 ,  Peggy Scherle  1 ,  Wenqing Yao  1 ,  Xiaozhao Wang  1
Affiliations
  • 1. Incyte Research Institute, Incyte Corporation, Wilmington, Delaware19803, United States.
PMID: 42201333 DOI: 10.1021/acs.jmedchem.6c00964
Abstract

Suppression of immune checkpoint pathways enables tumor cells to take over immunoregulatory functions, promoting cell growth and proliferation. Elevated adenosine production in the tumor microenvironment suppresses immune checkpoint control through activation of A2A adenosine receptors on immune cells. While A2A antagonists originally developed for CNS indications have entered oncology, their potency may be insufficient to challenge locally high adenosine concentrations within the tumor microenvironment for receptor occupancy. Here, we describe the discovery of INCB106385 (36), a potent dual A2A/A2B antagonist identified from in-house screening efforts. Compound 36 exhibits high potency at both receptors, favorable drug-like properties, and limited CNS penetration. In preclinical studies, it demonstrated robust pharmacokinetics across species and significant efficacy in a multiday CT26 mouse colon carcinoma model. These findings supported the advancement of INCB106385 into Phase 1 clinical trials (NCT04580485, NCT04989387) for Cancer Immunotherapy.

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