7MU6

Ask1 bound to compound 28

This is a non-PDB format compatible entry.

Summary for 7MU6

• Entry DOI: 10.2210/pdb7mu6/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase 5, 2-methoxy-N-(6-{4-[(2S)-1,1,1-trifluoropropan-2-yl]-4H-1,2,4-triazol-3-yl}pyridin-2-yl)pyridine-3-carboxamide (3 entities in total)
• Functional Keywords: ask1, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 75821.58

Authors

Chodaparambil, J.V.,Marcotte, D.J. (deposition date: 2021-05-14, release date: 2024-07-17)

Primary citation

Jones, J.H.,Xin, Z.,Himmelbauer, M.,Dechantsreiter, M.,Enyedy, I.,Hedde, J.,Fang, T.,Coomaraswamy, J.,King, K.W.,Murugan, P.,Santoro, J.C.,Hesson, T.,Walther, D.M.,Wei, R.,Zheng, F.,Marcotte, D.J.,Spilker, K.,Kumar, P.R.,Liu, Y.,Gilfillan, R.,Gonzalez-Lopez de Turiso, F.
Discovery of Potent, Selective, and Brain-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors that Modulate Brain Inflammation In Vivo.
J.Med.Chem., 64:15402-15419, 2021

PubMed Abstract: Apoptosis signal-regulating kinase 1 (ASK1) is one of the key mediators of the cellular stress response that regulates inflammation and apoptosis. To probe the therapeutic value of modulating this pathway in preclinical models of neurological disease, we further optimized the profile of our previously reported inhibitor . This effort led to the discovery of , a potent (cell IC = 25 nM) and selective ASK1 inhibitor with suitable pharmacokinetic and brain penetration (rat Cl/Cl = 1.6/56 L/h/kg and = 0.46) for proof-of-pharmacology studies. Specifically, the ability of to inhibit ASK1 in the central nervous system (CNS) was evaluated in a human tau transgenic (Tg4510) mouse model exhibiting elevated brain inflammation. In this study, transgenic animals treated with (at 3, 10, and 30 mg/kg, BID/PO for 4 days) showed a robust reduction of inflammatory markers (, IL-1β) in the cortex, thus confirming inhibition of ASK1 in the CNS.

PubMed: 34653340
DOI: 10.1021/acs.jmedchem.1c01458

Experimental method

X-RAY DIFFRACTION (2.165 Å)