A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models.

Autor: Ren F; Insilico Medicine Shanghai Ltd., Shanghai, China.; Insilico Medicine AI Limited, Abu Dhabi, UAE., Aliper A; Insilico Medicine AI Limited, Abu Dhabi, UAE.; Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong SAR, China., Chen J; Department of Clinical Pharmacology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China., Zhao H; Insilico Medicine Shanghai Ltd., Shanghai, China., Rao S; Insilico Medicine US Inc., New York, NY, USA., Kuppe C; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.; Department of Nephrology, University Clinic RWTH Aachen, Aachen, Germany., Ozerov IV; Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong SAR, China., Zhang M; Insilico Medicine Shanghai Ltd., Shanghai, China., Witte K; Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong SAR, China., Kruse C; Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong SAR, China., Aladinskiy V; Insilico Medicine AI Limited, Abu Dhabi, UAE., Ivanenkov Y; Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong SAR, China., Polykovskiy D; Insilico Medicine Canada Inc, Montreal, Quebec, Canada., Fu Y; Insilico Medicine Shanghai Ltd., Shanghai, China., Babin E; Insilico Medicine AI Limited, Abu Dhabi, UAE., Qiao J; Insilico Medicine Shanghai Ltd., Shanghai, China., Liang X; Insilico Medicine Shanghai Ltd., Shanghai, China., Mou Z; Insilico Medicine Shanghai Ltd., Shanghai, China., Wang H; Insilico Medicine Shanghai Ltd., Shanghai, China., Pun FW; Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong SAR, China., Torres-Ayuso P; Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, PA, USA., Veviorskiy A; Insilico Medicine AI Limited, Abu Dhabi, UAE., Song D; Department of Clinical Pharmacology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China., Liu S; Insilico Medicine Shanghai Ltd., Shanghai, China., Zhang B; Insilico Medicine Shanghai Ltd., Shanghai, China., Naumov V; Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong SAR, China., Ding X; Division of Nephrology, Zhongshan Hospital Shanghai Medical College, Fudan University, Shanghai, China., Kukharenko A; Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong SAR, China., Izumchenko E; Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA., Zhavoronkov A; Insilico Medicine AI Limited, Abu Dhabi, UAE. alex@insilico.com.; Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong SAR, China. alex@insilico.com.; Insilico Medicine US Inc., New York, NY, USA. alex@insilico.com.; Insilico Medicine Canada Inc, Montreal, Quebec, Canada. alex@insilico.com.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2024 Mar 08. Date of Electronic Publication: 2024 Mar 08.
DOI: 10.1038/s41587-024-02143-0
Abstrakt: Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as an anti-fibrotic target using a predictive artificial intelligence (AI) approach. Using AI-driven methodology, we generated INS018_055, a small-molecule TNIK inhibitor, which exhibits desirable drug-like properties and anti-fibrotic activity across different organs in vivo through oral, inhaled or topical administration. INS018_055 possesses anti-inflammatory effects in addition to its anti-fibrotic profile, validated in multiple in vivo studies. Its safety and tolerability as well as pharmacokinetics were validated in a randomized, double-blinded, placebo-controlled phase I clinical trial (NCT05154240) involving 78 healthy participants. A separate phase I trial in China, CTR20221542, also demonstrated comparable safety and pharmacokinetic profiles. This work was completed in roughly 18 months from target discovery to preclinical candidate nomination and demonstrates the capabilities of our generative AI-driven drug-discovery pipeline.
(© 2024. The Author(s).)
Databáze: MEDLINE
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