9HJQ

ROCK2 bound with TDI01

This is a non-PDB format compatible entry.

Summary for 9HJQ

• Entry DOI: 10.2210/pdb9hjq/pdb
• EMDB information: 52224
• Descriptor: Rho-associated protein kinase 2, [3,3-bis(fluoranyl)azetidin-1-yl]-[1-methyl-6-[4-[[4-(1~{H}-pyrazol-4-yl)phenyl]amino]pyrimidin-2-yl]indol-2-yl]methanone (2 entities in total)
• Functional Keywords: inhibitor, kinase, transferase, cytosolic protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 92829.43

Authors

Aijia, W.,Shenghai, C.,Qinghua, L.,Yan, H.,Haohao, D.,Bisen, D. (deposition date: 2024-11-30, release date: 2026-06-17, Last modification date: 2026-07-01)

Primary citation

Hu, Y.,Yang, B.,Xiao, C.,Yang, X.,Zhang, H.,Yang, P.,Du, X.,Zhang, G.,Liang, B.,Bai, N.,Zhang, D.,Wu, D.,Luo, Q.,Teng, Y.,Chen, Y.,Guo, Z.,Zhao, C.,Ye, T.,Chai, D.,Qi, X.,Zhong, W.,Chen, J.,Dong, H.,Gao, J.,He, H.,Chang, J.,Li, X.,Peng, L.,Rafii, S.,Friedman, S.L.,Yi, C.,Cai, Y.,Zhao, Y.,Wang, H.,Wang, C.,Cao, Z.,Ding, B.S.
Selective targeting of endothelial and perivascular angiocrine ROCK2 treats liver fibrosis.
Cell, 189:2663-2683.e26, 2026

PubMed Abstract: Liver fibrosis is a prominent pathological process contributing to death from hepatic diseases, including metabolic dysfunction-associated steatohepatitis (MASH). There is limited treatment for liver fibrosis. Here, we find that upregulation of Rho-associated coiled-coil containing kinase 2 (ROCK2) in liver endothelial cells (ECs) and perivascular hepatic stellate cells (HSCs) causes vascular niche dysfunction and triggers pro-fibrotic angiocrine signaling. Based on the vascular druggable target ROCK2, we developed its selective inhibitor showing anti-fibrotic potency in preclinical models and human patients. The ROCK2-selective inhibitor TDI01 restored vascular phenotype and alleviated fibrosis in rodent and minipig MASH models. A phase 1 clinical trial (ChiCTR2200058868) of TDI01 demonstrated its favorable pharmacokinetics and safety in humans. An extended clinical trial (ChiCTR2400082056) showed a trend toward reducing liver fibrosis in five of six patients after TDI01 treatment. Thus, we discover vascular ROCK2 as a pro-fibrotic target, and development of an inhibitor selectively targeting angiocrine ROCK2 may provide a treatment of liver fibrosis in human patients.

PubMed: 41794026
DOI: 10.1016/j.cell.2026.02.001

Experimental method

ELECTRON MICROSCOPY (3.8 Å)