Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• ACS medicinal chemistry letters, 2020-04, Vol.11 (4), p.550-557

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.