2. Academic Validation
  3. INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology

INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology

  • ACS Med Chem Lett. 2017 Mar 6;8(5):486-491. doi: 10.1021/acsmedchemlett.6b00391.
Eddy W Yue 1,  Richard Sparks 1,  Padmaja Polam 1,  Dilip Modi 1,  Brent Douty 1,  Brian Wayland 1,  Brian Glass 1,  Amy Takvorian 1,  Joseph Glenn 1,  Wenyu Zhu 1,  Michael Bower 1,  Xiangdong Liu 1,  Lynn Leffet 1,  Qian Wang 1,  Kevin J Bowman 1,  Michael J Hansbury 1,  Min Wei 1,  Yanlong Li 1,  Richard Wynn 1,  Timothy C Burn 1,  Holly K Koblish 1,  Jordan S Fridman 1,  Tom Emm 1,  Peggy A Scherle 1,  Brian Metcalf 1,  Andrew P Combs 1
Affiliations

Affiliation

  • 1 Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
PMID: 28523098 DOI: 10.1021/acsmedchemlett.6b00391
Abstract

A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 Inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.

Keywords

Epacadostat; IDO1; INCB24360; data-centric medicinal chemistry; immuno-oncology.

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