TY - JOUR
T1 - Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy
AU - Mitcheltree, Matthew J.
AU - Li, Derun
AU - Achab, Abdelghani
AU - Beard, Adam
AU - Chakravarthy, Kalyan
AU - Cheng, Mangeng
AU - Cho, Hyelim
AU - Eangoor, Padmanabhan
AU - Fan, Peter
AU - Gathiaka, Symon
AU - Kim, Hai-Young
AU - Lesburg, Charles A.
AU - Lyons, Thomas W.
AU - Martinot, Theodore A.
AU - Miller, J. Richard
AU - McMinn, Spencer
AU - O'Neil, Jennifer
AU - Palani, Anandan
AU - Palte, Rachel L.
AU - Sauri, Josep
AU - Sloman, David L.
AU - Zhang, Hongjun
AU - Cumming, Jared N.
AU - Fischer, Christian
PY - 2020/4/9
Y1 - 2020/4/9
N2 - The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzymeinhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored.
AB - The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzymeinhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored.
KW - Arginase inhibitor
KW - Cancer immunotherapy
KW - Pharmacokinetic optimization
KW - Structure-based drug design
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000526402700027&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1021/acsmedchemlett.0c00058
DO - 10.1021/acsmedchemlett.0c00058
M3 - Article
C2 - 32292567
SN - 1948-5875
VL - 11
SP - 582
EP - 588
JO - Acs Medicinal Chemistry Letters
JF - Acs Medicinal Chemistry Letters
IS - 4
ER -
