PDBsum entry 3coh

Transferase

PDB id: 3coh

Contents

Protein chains

247 a.a. *

Ligands

83H ×2

* Residue conservation analysis

PDB id:

3coh

Name:

Transferase

Title:

Crystal structure of aurora-a in complex with a pentacyclic inhibitor

Structure:

Serine/threonine-protein kinase 6. Chain: a, b. Fragment: kinase domain (unp residues 124-391). Synonym: aurora kinase a, aurora-a, serine/threonine kinase 15, aurora/ipl1-related kinase 1, aurora-related kinase 1, hark1, breast tumor-amplified kinase. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: aurka, aik, ark1, aura, btak, stk15, stk6. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.70Å R-factor: 0.248 R-free: 0.280

Authors:

C.Wiesmann,T.E.Raswson,A.G.Cochran

Key ref:

T.E.Rawson et al. (2008). A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability. J Med Chem, 51, 4465-4475. PubMed id: 18630890

Date:

28-Mar-08 Release date: 17-Feb-09

Protein chains

O14965  (AURKA_HUMAN) -  Aurora kinase A from Homo sapiens

Seq: 403 a.a.

Struc: 247 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

J Med Chem 51:4465-4475 (2008)

PubMed id: 18630890

A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability.

T.E.Rawson, M.Rüth, E.Blackwood, D.Burdick, L.Corson, J.Dotson, J.Drummond, C.Fields, G.J.Georges, B.Goller, J.Halladay, T.Hunsaker, T.Kleinheinz, H.W.Krell, J.Li, J.Liang, A.Limberg, A.McNutt, J.Moffat, G.Phillips, Y.Ran, B.Safina, M.Ultsch, L.Walker, C.Wiesmann, B.Zhang, A.Zhou, B.Y.Zhu, P.Rüger, A.G.Cochran.

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.