5KQ5

AMPK bound to allosteric activator

Summary for 5KQ5

• Entry DOI: 10.2210/pdb5kq5/pdb
• Descriptor: 5'-AMP-activated protein kinase catalytic subunit alpha-1, 5'-AMP-activated protein kinase subunit beta-1, 5'-AMP-activated protein kinase subunit gamma-1, ... (9 entities in total)
• Functional Keywords: kinase allosteric activator, transferase
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm : P54645
• Total number of polymer chains: 3
• Total formula weight: 120426.34

Authors

Calabrese, M.F.,Kurumbail, R.G. (deposition date: 2016-07-05, release date: 2016-08-17, Last modification date: 2024-10-16)

Primary citation

Cameron, K.O.,Kung, D.W.,Kalgutkar, A.S.,Kurumbail, R.G.,Miller, R.,Salatto, C.T.,Ward, J.,Withka, J.M.,Bhattacharya, S.K.,Boehm, M.,Borzilleri, K.A.,Brown, J.A.,Calabrese, M.,Caspers, N.L.,Cokorinos, E.,Conn, E.L.,Dowling, M.S.,Edmonds, D.J.,Eng, H.,Fernando, D.P.,Frisbie, R.,Hepworth, D.,Landro, J.,Mao, Y.,Rajamohan, F.,Reyes, A.R.,Rose, C.R.,Ryder, T.,Shavnya, A.,Smith, A.C.,Tu, M.,Wolford, A.C.,Xiao, J.
Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy.
J.Med.Chem., 59:8068-8081, 2016

PubMed Abstract: Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.

PubMed: 27490827
DOI: 10.1021/acs.jmedchem.6b00866

Experimental method

X-RAY DIFFRACTION (3.41 Å)