8ZML

Structure of TNIK with inhibitor

This is a non-PDB format compatible entry.

Summary for 8ZML

• Entry DOI: 10.2210/pdb8zml/pdb
• Descriptor: TRAF2 and NCK-interacting protein kinase, Rentosertib, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: inhibitor, cell cycle
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 70873.77

Authors

Fan, Y. (deposition date: 2024-05-23, release date: 2025-05-28, Last modification date: 2025-12-10)

Primary citation

Aladinskiy, V.,Kruse, C.,Qin, L.,Babin, E.,Fan, Y.,Andreev, G.,Zhao, H.,Fu, Y.,Zhang, M.,Ivanenkov, Y.,Aliper, A.,Zhavoronkov, A.,Ren, F.
Discovery of Bis-imidazolecarboxamide Derivatives as Novel, Potent, and Selective TNIK Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis.
J.Med.Chem., 67:19121-19142, 2024

PubMed Abstract: Traf2- and Nck-interacting kinase (TNIK) has been identified as a promising therapeutic target for the treatment of fibrosis-driven diseases. Utilizing a structure-based drug design workflow, we developed a series of potent TNIK inhibitors that modulate the conformation of the gatekeeper Met105 side chain and access the TNIK back pocket. The lead optimization efforts culminated in the discovery of the recently reported compound (INS018_055), a novel TNIK inhibitor. This molecule demonstrated excellent activity in both enzymatic and cell-based assays, along with high selectivity in a kinome panel. Further, and preclinical studies revealed favorable and DMPK properties. Results from multiple cell-based and animal models proved that compound exhibits considerable antifibrotic and anti-inflammatory efficacy. Currently, phase II clinical trials of compound are underway for the treatment of idiopathic pulmonary fibrosis (IPF).

PubMed: 39422731
DOI: 10.1021/acs.jmedchem.4c01580

Experimental method

X-RAY DIFFRACTION (2.489 Å)