3COH

Crystal structure of Aurora-A in complex with a pentacyclic inhibitor

Summary for 3COH

• Entry DOI: 10.2210/pdb3coh/pdb
• Descriptor: Serine/threonine-protein kinase 6, 8-ethyl-3,10,10-trimethyl-4,5,6,8,10,12-hexahydropyrazolo[4',3':6,7]cyclohepta[1,2-b]pyrrolo[2,3-f]indol-9(1H)-one (2 entities in total)
• Functional Keywords: aurora-a, inhibitor complex, atp-binding, cell cycle, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytoskeleton, centrosome: O14965
• Total number of polymer chains: 2
• Total formula weight: 62712.19

Authors

Wiesmann, C.,Raswson, T.E.,Cochran, A.G. (deposition date: 2008-03-28, release date: 2009-02-17, Last modification date: 2024-10-30)

Primary citation

Rawson, T.E.,Ruth, M.,Blackwood, E.,Burdick, D.,Corson, L.,Dotson, J.,Drummond, J.,Fields, C.,Georges, G.J.,Goller, B.,Halladay, J.,Hunsaker, T.,Kleinheinz, T.,Krell, H.W.,Li, J.,Liang, J.,Limberg, A.,McNutt, A.,Moffat, J.,Phillips, G.,Ran, Y.,Safina, B.,Ultsch, M.,Walker, L.,Wiesmann, C.,Zhang, B.,Zhou, A.,Zhu, B.Y.,Ruger, P.,Cochran, A.G.
A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability.
J.Med.Chem., 51:4465-4475, 2008

PubMed Abstract: Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and compares favorably to a previously reported Aurora inhibitor, 39 (VX-680). The inhibitor exhibits low nanomolar potency against both Aurora A and Aurora B enzymes, excellent cellular potency (IC50 < 100 nM), and good oral bioavailability. Phenotypic cellular assays show that both Aurora A and Aurora B are inhibited at inhibitor concentrations sufficient to block proliferation. Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model.

PubMed: 18630890
DOI: 10.1021/jm800052b

Experimental method

X-RAY DIFFRACTION (2.7 Å)