3MYG

Aurora A Kinase complexed with SCH 1473759

Summary for 3MYG

• Entry DOI: 10.2210/pdb3myg/pdb
• Descriptor: Serine/threonine-protein kinase 6, TETRAETHYLENE GLYCOL, 2-{ethyl[(5-{[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino}isothiazol-3-yl)methyl]amino}-2-methylpropan-1-ol, ... (4 entities in total)
• Functional Keywords: kinase, cell cycle, inhibitor, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : O14965
• Total number of polymer chains: 1
• Total formula weight: 32060.91

Authors

Hruza, A.,Prosis, W.,Ramanathan, L. (deposition date: 2010-05-10, release date: 2010-07-21, Last modification date: 2023-09-06)

Primary citation

Yu, T.,Tagat, J.R.,Kerekes, A.D.,Doll, R.J.,Zhang, Y.,Xiao, Y.,Esposite, S.,Belanger, D.B.,Curran, P.J.,Mandal, A.K.,Siddiqui, M.A.,Shih, N.Y.,Basso, A.D.,Liu, M.,Gray, K.,Tevar, S.,Jones, J.,Lee, S.,Liang, L.,Ponery, S.,Smith, E.B.,Hruza, A.,Voigt, J.,Ramanathan, L.,Prosise, W.,Hu, M.
Discovery of a Potent, Injectable Inhibitor of Aurora Kinases Based on the Imidazo-[1,2-a]-Pyrazine Core.
ACS Med Chem Lett, 1:214-218, 2010

PubMed Abstract: The imidazo-[1,2-a]-pyrazine (1) is a dual inhibitor of Aurora kinases A and B with modest cell potency (IC50 = 250 nM) and low solubility (5 μM). Lead optimization guided by the binding mode led to the acyclic amino alcohol 12k (SCH 1473759), which is a picomolar inhibitor of Aurora kinases (TdF K d Aur A = 0.02 nM and Aur B = 0.03 nM) with improved cell potency (phos-HH3 inhibition IC50 = 25 nM) and intrinsic aqueous solubility (11.4 mM). It also demonstrated efficacy and target engagement in human tumor xenograft mouse models.

PubMed: 24900197
DOI: 10.1021/ml100063w

Experimental method

X-RAY DIFFRACTION (2.4 Å)