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Conformational-Analysis-Guided Discovery of 2,3-Disubstituted Pyridine IDO1 Inhibitors.


ABSTRACT: IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1 inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that, while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this quinoline with an alternative aromatic system led to the discovery of 2,3-disubstituted pyridines as suitable replacements. Further optimization, which included lowering ClogP in combination with strategic fluorine incorporation, led to the discovery of compound 29, a potent, selective IDO1 inhibitor with robust pharmacodynamic activity in a mouse xenograft model.

SUBMITTER: Cherney EC 

PROVIDER: S-EPMC8274105 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Conformational-Analysis-Guided Discovery of 2,3-Disubstituted Pyridine IDO1 Inhibitors.

Cherney Emily C EC   Zhang Liping L   Guo Weiwei W   Huang Audris A   Williams David D   Seitz Steven S   Shan Weifang W   Zhu Xiao X   Gullo-Brown Johnni J   Maley Derrick D   Lin Tai-An TA   Hunt John T JT   Huang Christine C   Yang Zheng Z   D'Arienzo Celia J CJ   Discenza Lorell N LN   Ranasinghe Asoka A   Grubb Mary F MF   Traeger Sarah C SC   Li Xin X   Johnston Kathy A KA   Kopcho Lisa L   Fereshteh Mark M   Foster Kimberly A KA   Stefanski Kevin K   Delpy Diane D   Dhar Gopal G   Anandam Aravind A   Mahankali Sandeep S   Padmanabhan Shweta S   Rajanna Prabhakar P   Murali Venkata V   Mariappan T Thanga TT   Pattasseri Shabeerali S   Nimje Roshan Y RY   Hong Zhenqiu Z   Kempson James J   Rampulla Richard R   Mathur Arvind A   Gupta Anuradha A   Borzilleri Robert R   Vite Gregory G   Balog Aaron A  

ACS medicinal chemistry letters 20210616 7


IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1 inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that, while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this quinoline wi  ...[more]

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