9HY8

Crystal structure of an allosteric inhibitor bound to human RIPK1 kinase domain

This is a non-PDB format compatible entry.

Summary for 9HY8

• Entry DOI: 10.2210/pdb9hy8/pdb
• Descriptor: Receptor-interacting serine/threonine-protein kinase 1, 1-[2,5-bis(chloranyl)phenyl]carbonyl-~{N}-[(4-methylphenyl)methyl]piperidine-4-carboxamide, IODIDE ION, ... (5 entities in total)
• Functional Keywords: ripk1, kinase, inhibitor, complex, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 68812.29

Authors

Maskos, K.,Johannsson, S.,Kempf, G.,Neumann, L.,Cross, J.B. (deposition date: 2025-01-09, release date: 2025-12-24, Last modification date: 2026-01-28)

Primary citation

Vijayan, R.S.K.,Hamilton, M.M.,Pfaffinger, D.E.,Alvarez, F.G.,Reyna, N.J.,Bardenhagen, J.P.,Shepard, H.,Rodriguez, C.,Goodwani, S.,Lightfoot, Y.,Maskos, K.,Johannsson, S.,Kempf, G.,Xu, Q.A.,Neumann, L.,Jiang, Y.,Do, M.G.,Jones, P.,Lewis, R.T.,Ray, W.J.,Cross, J.B.
Allosteric targeting of RIPK1: discovery of novel inhibitors via parallel virtual screening and structure-guided optimization.
Rsc Med Chem, 16:5341-5358, 2025

PubMed Abstract: Receptor-interacting serine/threonine protein-kinase 1 (RIPK1) is a critical signalling protein that regulates inflammation and cell death in response to TNF signalling. Inhibiting RIPK1 kinase activity prevents neuronal cell death in various animal models, making it a promising therapeutic target for neurodegenerative, inflammatory, and autoimmune disorders. To identify novel allosteric RIPK1 inhibitors, we used a parallel virtual screening strategy that employed structure-based pharmacophore, shape-based, and fuzzy pharmacophore similarity approaches. Structure-guided optimization enabled by X-ray crystallography led to the discovery of a potent and selective piperidinecarboxamide inhibitor with an acceptable pharmacokinetic (PK) profile and limited brain exposure. This work highlights the effectiveness of virtual screening, followed by structure-guided optimization, in identifying progressible allosteric kinase inhibitors.

PubMed: 40969564
DOI: 10.1039/d5md00317b

Experimental method

X-RAY DIFFRACTION (2.98 Å)