2. Academic Validation
  3. A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models

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

  • Nat Biotechnol. 2025 Jan;43(1):63-75. doi: 10.1038/s41587-024-02143-0.
Feng Ren 1 2,  Alex Aliper 2 3,  Jian Chen 4,  Heng Zhao 1,  Sujata Rao 5,  Christoph Kuppe 6 7,  Ivan V Ozerov 3,  Man Zhang 1,  Klaus Witte 3,  Chris Kruse 3,  Vladimir Aladinskiy 2,  Yan Ivanenkov 3,  Daniil Polykovskiy 8,  Yanyun Fu 1,  Eugene Babin 2,  Junwen Qiao 1,  Xing Liang 1,  Zhenzhen Mou 1,  Hui Wang 1,  Frank W Pun 3,  Pedro Torres-Ayuso 9,  Alexander Veviorskiy 2,  Dandan Song 4,  Sang Liu 1,  Bei Zhang 1,  Vladimir Naumov 3,  Xiaoqiang Ding 10,  Andrey Kukharenko 3,  Evgeny Izumchenko 11,  Alex Zhavoronkov 12 13 14 15
Affiliations

Affiliations

  • 1 Insilico Medicine Shanghai Ltd., Shanghai, China.
  • 2 Insilico Medicine AI Limited, Abu Dhabi, UAE.
  • 3 Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong SAR, China.
  • 4 Department of Clinical Pharmacology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China.
  • 5 Insilico Medicine US Inc., New York, NY, USA.
  • 6 Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.
  • 7 Department of Nephrology, University Clinic RWTH Aachen, Aachen, Germany.
  • 8 Insilico Medicine Canada Inc, Montreal, Quebec, Canada.
  • 9 Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, PA, USA.
  • 10 Division of Nephrology, Zhongshan Hospital Shanghai Medical College, Fudan University, Shanghai, China.
  • 11 Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
  • 12 Insilico Medicine AI Limited, Abu Dhabi, UAE. alex@insilico.com.
  • 13 Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong SAR, China. alex@insilico.com.
  • 14 Insilico Medicine US Inc., New York, NY, USA. alex@insilico.com.
  • 15 Insilico Medicine Canada Inc, Montreal, Quebec, Canada. alex@insilico.com.
PMID: 38459338 DOI: 10.1038/s41587-024-02143-0
Abstract

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.

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