posted on 2020-03-13, 17:33authored byCatherine White, Meredeth A. McGowan, Hua Zhou, Nunzio Sciammetta, Xavier Fradera, Jongwon Lim, Elizabeth M. Joshi, Christine Andrews, Elliott B. Nickbarg, Phillip Cowley, Sarah Trewick, Martin Augustin, Konstanze von Köenig, Charles A. Lesburg, Karin Otte, Ian Knemeyer, Hyun Woo, Wensheng Yu, Mangeng Cheng, Peter Spacciapoli, Prasanthi Geda, Xuelei Song, Nadya Smotrov, Patrick Curran, Mee Ra Heo, Pravien Abeywickrema, J. Richard Miller, David Jonathan Bennett, Yongxin Han
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.