6CMJ

Human CAMKK2 with GSK650393

Summary for 6CMJ

• Entry DOI: 10.2210/pdb6cmj/pdb
• Descriptor: Calcium/calmodulin-dependent protein kinase kinase 2, 2-(2-methylpropyl)-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid, FORMIC ACID, ... (5 entities in total)
• Functional Keywords: kinase, signaling protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q96RR4
• Total number of polymer chains: 2
• Total formula weight: 74628.44

Authors

Williams, S.P.,Reid, R.A.,Price, D.J.,Drewry, D.H. (deposition date: 2018-03-05, release date: 2018-04-04, Last modification date: 2024-11-20)

Primary citation

Price, D.J.,Drewry, D.H.,Schaller, L.T.,Thompson, B.D.,Reid, P.R.,Maloney, P.R.,Liang, X.,Banker, P.,Buckholz, R.G.,Selley, P.K.,McDonald, O.B.,Smith, J.L.,Shearer, T.W.,Cox, R.F.,Williams, S.P.,Reid, R.A.,Tacconi, S.,Faggioni, F.,Piubelli, C.,Sartori, I.,Tessari, M.,Wang, T.Y.
An orally available, brain-penetrant CAMKK2 inhibitor reduces food intake in rodent model.
Bioorg. Med. Chem. Lett., 28:1958-1963, 2018

PubMed Abstract: Hypothalamic CAMKK2 represents a potential mechanism for chemically affecting satiety and promoting weight loss in clinically obese patients. Single-digit nanomolar inhibitors of CAMKK2 were identified in three related ATP-competitive series. Limited optimization of kinase selectivity, solubility, and pharmacokinetic properties were undertaken on all three series, as SAR was often transferrable. Ultimately, a 2,4-diaryl 7-azaindole was optimized to afford a tool molecule that potently inhibits AMPK phosphorylation in a hypothalamus-derived cell line, is orally bioavailable, and crosses the blood-brain barrier. When dosed orally in rodents, compound 4 t limited ghrelin-induced food intake.

PubMed: 29653895
DOI: 10.1016/j.bmcl.2018.03.034

Experimental method

X-RAY DIFFRACTION (2.4 Å)