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Discovery of 4-Azaindole Inhibitors of TGF?RI as Immuno-oncology Agents.

ABSTRACT: The multifunctional cytokine TGF? plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGF? signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGF? receptor kinase inhibitors with excellent selectivity for TGF? receptor 1 kinase. The combination of compound 3f and an antimouse-PD-1 antibody demonstrated significantly improved antitumor efficacy compared to either treatment alone in a murine tumor model.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6231184 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Discovery of 4-Azaindole Inhibitors of TGFβRI as Immuno-oncology Agents.

Zhang Yong Y Zhao Yufen Y Tebben Andrew J AJ Sheriff Steven S Ruzanov Max M Fereshteh Mark P MP Fan Yi Y Lippy Jonathan J Swanson Jesse J Ho Ching-Ping CP Wautlet Barri S BS Rose Anne A Parrish Karen K Yang Zheng Z Donnell Andrew F AF Zhang Liping L Fink Brian E BE Vite Gregory D GD Augustine-Rauch Karen K Fargnoli Joseph J Borzilleri Robert M RM

ACS medicinal chemistry letters 20181017 11

The multifunctional cytokine TGFβ plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFβ signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFβ receptor kinase inhibitors with excellent selectivity for TGFβ receptor 1 kinase. The combination of compound <b>3f</b> and an antimouse-PD-1 antibody demonstrated significantly improved antitumor ...[more]

PMID: 30429955

Dataset Information

Discovery of 4-Azaindole Inhibitors of TGF?RI as Immuno-oncology Agents.

Publications

Discovery of 4-Azaindole Inhibitors of TGFβRI as Immuno-oncology Agents.

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