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, Torres-Ayuso Pedro, Veviorskiy Alexander, Song Dandan, Liu Sang, Zhang Bei, Naumov Vladimir, Ding Xiaoqiang, Kukharenko Andrey, Izumchenko Evgeny, Zhavoronkov Alex
Insilico Medicine Shanghai Ltd., Shanghai, China.
Insilico Medicine AI Limited, Abu Dhabi, UAE.
Nat Biotechnol. 2025 Jan;43(1):63-75. doi: 10.1038/s41587-024-02143-0. Epub 2024 Mar 8.
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.
特发性肺纤维化（IPF）是一种侵袭性间质性肺疾病，死亡率很高。IPF中假定的药物靶点在临床层面未能转化为有效的治疗方法。我们使用预测性人工智能（AI）方法将肿瘤坏死因子受体相关因子2和NCK相互作用激酶（TNIK）鉴定为抗纤维化靶点。利用人工智能驱动的方法，我们开发了INS018_055，一种小分子TNIK抑制剂，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除了具有抗纤维化作用外，还具有抗炎作用，这在多项体内研究中得到了验证。其安全性、耐受性以及药代动力学在一项涉及78名健康参与者的随机、双盲、安慰剂对照的I期临床试验（NCT05154240）中得到了验证。在中国进行的另一项I期试验CTR20221542也证明了类似的安全性和药代动力学特征。这项工作从靶点发现到临床前候选药物提名大约用了18个月完成，展示了我们基于生成式人工智能的药物发现流程的能力。
