ACS Medicinal Chemistry Letters p. 550 - 557 (2020)
Update date:2022-08-03
Topics:
Abeywickrema, Pravien
Andrews, Christine
Augustin, Martin
Bennett, David Jonathan
Cheng, Mangeng
Cowley, Phillip
Curran, Patrick
Fradera, Xavier
Geda, Prasanthi
Han, Yongxin
Heo, Mee Ra
Joshi, Elizabeth M.
Knemeyer, Ian
Lesburg, Charles A.
Lim, Jongwon
McGowan, Meredeth A.
Miller, J. Richard
Nickbarg, Elliott B.
Otte, Karin
Sciammetta, Nunzio
Smotrov, Nadya
Song, Xuelei
Spacciapoli, Peter
Trewick, Sarah
Von K?enig, Konstanze
White, Catherine
Woo, Hyun
Yu, Wensheng
Zhou, Hua
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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