2. Academic Validation
  3. Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy

Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy

  • ACS Med Chem Lett. 2019 Sep 18;10(11):1530-1536. doi: 10.1021/acsmedchemlett.9b00344.
Hongjun Zhang 1,  Kun Liu 1,  Qinglin Pu 1,  Abdelghani Achab 1,  Michael J Ardolino 1,  Mangeng Cheng 1,  Yongqi Deng 1,  Amy C Doty 1,  Heidi Ferguson 1,  Xavier Fradera 1,  Ian Knemeyer 1,  Ravi Kurukulasuriya 1,  Yu-Hong Lam 2,  Charles A Lesburg 1,  Theodore A Martinot 1,  Meredeth A McGowan 1,  J Richard Miller 1,  Karin Otte 1,  Purakattle J Biju 1,  Nunzio Sciammetta 1,  Nicolas Solban 1,  Wensheng Yu 2,  Hua Zhou 1,  Xiao Wang 2,  David Jonathan Bennett 1,  Yongxin Han 1
Affiliations

Affiliations

  • 1 Departments of Discovery Chemistry, Discovery Process Chemistry, In Vitro & In Vivo Pharmacology, Discovery Pharmaceutical Sciences, Computational and Structural Chemistry, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • 2 Computational and Structural Chemistry, External Discovery Chemistry, and Analytical Research and Development, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
PMID: 31749906 DOI: 10.1021/acsmedchemlett.9b00344
Abstract

Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust SNAr reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound 16 was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound 16, rendering it a potential drug candidate.

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