2W1H

Fragment-Based Discovery of the Pyrazol-4-yl urea (AT9283), a Multi- targeted Kinase Inhibitor with Potent Aurora Kinase Activity

Summary for 2W1H

• Entry DOI: 10.2210/pdb2w1h/pdb
• Related: 1AQ1 1B38 1B39 1BUH 1CKP 1DI8 1DM2 1E1V 1E1X 1E9H 1F5Q 1FIN 1FQ1 1FVT 1FVV 1G5S 1GIH 1GII 1GIJ 1GY3 1GZ8 1H00 1H01 1H07 1H08 1H0V 1H0W 1H1P 1H1Q 1H1R 1H1S 1H24 1H25 1H26 1H27 1H28 1HCK 1HCL 1JST 1JSU 1JSV 1JVP 1KE5 1KE6 1KE7 1KE8 1KE9 1OGU 1OI9 1OIQ 1OIR 1OIT 1OIU 1OIY 1OKV 1OKW 1OL1 1OL2 1P2A 1P5E 1PF8 1PKD 1PW2 1PXI 1PXJ 1PXK 1PXL 1PXM 1PXN 1PXO 1PXP 1PYE 1QMZ 1R78 1URC 1URW 1V1K 1VYW 1VYZ 1W0X 1W8C 1W98 1WCC 1Y8Y 1Y91 1YKR 2A0C 2A4L 2B52 2B53 2B54 2B55 2BHE 2BHH 2BKZ 2BPM 2BTR 2BTS 2C4G 2C5N 2C5O 2C5P 2C5V 2C5X 2C5Y 2C68 2C69 2C6I 2C6K 2C6L 2C6M 2C6O 2C6T 2CCH 2CCI 2CJM 2CLX 2EXM 2G9X 2IW6 2IW8 2IW9 2J9M 2JGZ 2UUE 2UZB 2UZD 2UZE 2UZL 2UZN 2UZO 2V0D 2V22 2VTA 2VTH 2VTI 2VTJ 2VTL 2VTM 2VTN 2VTO 2VTP 2VTQ 2VTR 2VTS 2VTT 2VU3 2VV9 2W05 2W06 2W17
• Descriptor: CELL DIVISION PROTEIN KINASE 2, N-[3-(1H-BENZIMIDAZOL-2-YL)-1H-PYRAZOL-4-YL]BENZAMIDE (3 entities in total)
• Functional Keywords: structure based drug design, kinase, mitosis, cell cycle, transferase, serine/threonine-protein kinase, atp-binding, polymorphism, cell division, phosphoprotein, fragment screening, nucleotide-binding
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm, cytoskeleton, centrosome: P24941
• Total number of polymer chains: 1
• Total formula weight: 34279.81

Authors

Howard, S.,Berdini, V.,Boulstridge, J.A.,Carr, M.G.,Cross, D.M.,Curry, J.,Devine, L.A.,Early, T.R.,Fazal, L.,Gill, A.L.,Heathcote, M.,Maman, S.,Matthews, J.E.,McMenamin, R.L.,Navarro, E.F.,O'Brien, M.A.,O'Reilly, M.,Rees, D.C.,Reule, M.,Tisi, D.,Williams, G.,Vinkovic, M.,Wyatt, P.G. (deposition date: 2008-10-17, release date: 2009-01-27, Last modification date: 2024-05-08)

Primary citation

Howard, S.,Berdini, V.,Boulstridge, J.A.,Carr, M.G.,Cross, D.M.,Curry, J.,Devine, L.A.,Early, T.R.,Fazal, L.,Gill, A.L.,Heathcote, M.,Maman, S.,Matthews, J.E.,Mcmenamin, R.L.,Navarro, E.F.,O'Brien, M.A.,O'Reilly, M.,Rees, D.C.,Reule, M.,Tisi, D.,Williams, G.,Vinkovic, M.,Wyatt, P.G.
Fragment-Based Discovery of the Pyrazol-4-Yl Urea (at9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity.
J.Med.Chem., 52:379-, 2009

PubMed Abstract: Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.

PubMed: 19143567
DOI: 10.1021/JM800984V

Experimental method

X-RAY DIFFRACTION (2.15 Å)