美国英矽智能公司Alex Zhavoronkov研究小组发现，一种小分子TNIK抑制剂在临床前和临床模型中靶向纤维化。2024年3月8日，国际知名学术期刊《自然—生物技术》在线发表了这一成果。

据研究人员介绍，特发性肺纤维化（IPF）是一种侵袭性间质性肺病，死亡率很高。IPF的潜在药物靶点未能转化为临床层面的有效疗法。

研究人员采用预测性人工智能（AI）方法，将TRAF2-与NCK相互作用激酶（TNIK）确定为抗纤维化靶点。利用人工智能驱动的方法，研究人员生成了一种小分子TNIK抑制剂INS018_055，它通过口服、吸入或局部给药，在体内不同器官中表现出理想的类药物特性和抗纤维化活性。INS018_055除具有抗纤维化特性外，还具有抗炎作用，这已在多项体内研究中得到验证。

一项随机、双盲、安慰剂对照的 I 期临床试验（NCT05154240）验证了INS018_055的安全性、耐受性和药代动力学，78名健康人参加了该试验。在中国进行的另一项I期临床试验（CTR20221542）也证明了该药物具有可比的安全性和药代动力学特征。从目标发现到临床前候选药物提名，这项工作在大约18个月内完成，展示了该生成式人工智能驱动药物发现管线的能力。

附：英文原文

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

Author: Ren, Feng, Aliper, Alex, Chen, Jian, Zhao, Heng, Rao, Sujata, Kuppe, Christoph, Ozerov, Ivan V., Zhang, Man, Witte, Klaus, Kruse, Chris, Aladinskiy, Vladimir, Ivanenkov, Yan, Polykovskiy, Daniil, Fu, Yanyun, Babin, Eugene, Qiao, Junwen, Liang, Xing, Mou, Zhenzhen, Wang, Hui, Pun, Frank W., Ayuso, Pedro Torres, Veviorskiy, Alexander, Song, Dandan, Liu, Sang, Zhang, Bei, Naumov, Vladimir, Ding, Xiaoqiang, Kukharenko, Andrey, Izumchenko, Evgeny, Zhavoronkov, Alex

Issue&Volume: 2024-03-08

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.

DOI: 10.1038/s41587-024-02143-0

Source: https://www.nature.com/articles/s41587-024-02143-0