7LGK

Crystal structure of soluble guanylate cyclase activator runcaciguat (BAY 1101042) bound to nostoc H-NOX domain

Summary for 7LGK

• Entry DOI: 10.2210/pdb7lgk/pdb
• Descriptor: H-NOX domain protein, Runcaciguat, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: soluble guanylyl cyclase, h-nox, signal transduction, activator, signaling protein, signaling protein-signaling protein activator complex, signaling protein-activator complex, signaling protein/activator
• Biological source: Nostoc sp. PCC 7120 = FACHB-418
• Total number of polymer chains: 2
• Total formula weight: 42317.72

Authors

van den Akker, F.,Kumar, V.,Schaefer, M. (deposition date: 2021-01-20, release date: 2021-05-05, Last modification date: 2023-10-18)

Primary citation

Hahn, M.G.,Lampe, T.,El Sheikh, S.,Griebenow, N.,Woltering, E.,Schlemmer, K.H.,Dietz, L.,Gerisch, M.,Wunder, F.,Becker-Pelster, E.M.,Mondritzki, T.,Tinel, H.,Knorr, A.,Kern, A.,Lang, D.,Hueser, J.,Schomber, T.,Benardeau, A.,Eitner, F.,Truebel, H.,Mittendorf, J.,Kumar, V.,van den Akker, F.,Schaefer, M.,Geiss, V.,Sandner, P.,Stasch, J.P.
Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042).
J.Med.Chem., 64:5323-5344, 2021

PubMed Abstract: Herein we describe the discovery, mode of action, and preclinical characterization of the soluble guanylate cyclase (sGC) activator runcaciguat. The sGC enzyme, via the formation of cyclic guanosine monophoshphate, is a key regulator of body and tissue homeostasis. sGC activators with their unique mode of action are activating the oxidized and heme-free and therefore NO-unresponsive form of sGC, which is formed under oxidative stress. The first generation of sGC activators like cinaciguat or ataciguat exhibited limitations and were discontinued. We overcame limitations of first-generation sGC activators and identified a new chemical class via high-throughput screening. The investigation of the structure-activity relationship allowed to improve potency and multiple solubility, permeability, metabolism, and drug-drug interactions parameters. This program resulted in the discovery of the oral sGC activator runcaciguat (compound , BAY 1101042). Runcaciguat is currently investigated in clinical phase 2 studies for the treatment of patients with chronic kidney disease and nonproliferative diabetic retinopathy.

PubMed: 33872507
DOI: 10.1021/acs.jmedchem.0c02154

Experimental method

X-RAY DIFFRACTION (2.2 Å)