2. Academic Validation
  3. Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1)

Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1)

  • ACS Med Chem Lett. 2020 Mar 10;11(4):550-557. doi: 10.1021/acsmedchemlett.0c00010.
Catherine White 1,  Meredeth A McGowan 1,  Hua Zhou 1,  Nunzio Sciammetta 1,  Xavier Fradera 1,  Jongwon Lim 1,  Elizabeth M Joshi 1,  Christine Andrews 1,  Elliott B Nickbarg 1,  Phillip Cowley 1,  Sarah Trewick 1,  Martin Augustin 2,  Konstanze von Köenig 2,  Charles A Lesburg 1,  Karin Otte 1,  Ian Knemeyer 1,  Hyun Woo 1,  Wensheng Yu 1,  Mangeng Cheng 1,  Peter Spacciapoli 1,  Prasanthi Geda 1,  Xuelei Song 1,  Nadya Smotrov 1,  Patrick Curran 1,  Mee Ra Heo 1,  Pravien Abeywickrema 1,  J Richard Miller 1,  David Jonathan Bennett 1,  Yongxin Han 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Computational and Structural Chemistry, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • 2 Proteros biostructures GmbH, 82152 Martinsried, Germany.
PMID: 32292563 DOI: 10.1021/acsmedchemlett.0c00010
Abstract

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of Cancer Immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a promising lead for the inhibition of IDO1. While hit 1 possessed attractive cell-based potency, it suffered from a significant right-shift in a whole blood assay, poor solubility, and poor pharmacokinetic properties. Through a physicochemical property-based approach, including a focus on lowering AlogP98 via the strategic introduction of polar substitution, compound 13 was identified bearing a pyridyl oxetane core. Compound 13 demonstrated improved whole blood potency and solubility, and an improved pharmacokinetic profile resulting in a low predicted human dose.

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