Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 8, Pages 1548-1554Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00195
Keywords
indoleamine-2,3-dioxygenase 1; IDO1; bicyclo[1.1.1]pentane; cancer immunotherapy
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Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.
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