2VTJ

Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H- pyrazole-3-carboxamide (AT7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design

Summary for 2VTJ

• Entry DOI: 10.2210/pdb2vtj/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 2VTL 2VTM 2VTN 2VTO 2VTP 2VTQ 2VTR 2VTS 2VTT 2VU3 2VV9
• Descriptor: CELL DIVISION PROTEIN KINASE 2, GLYCEROL, 4-[(6-chloropyrazin-2-yl)amino]benzenesulfonamide, ... (4 entities in total)
• Functional Keywords: transferase, mitosis, cell cycle, serine/threonine protein kinase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 34353.30

Authors

Wyatt, P.G.,Woodhead, A.J.,Boulstridge, J.A.,Berdini, V.,Carr, M.G.,Cross, D.M.,Danillon, D.,Davis, D.J.,Devine, L.A.,Early, T.R.,Feltell, R.E.,Lewis, E.J.,McMenamin, R.L.,Navarro, E.F.,O'Brien, M.A.,O'Reilly, M.,Reule, M.,Saxty, G.,Seavers, L.C.A.,Smith, D.,Squires, M.S.,Trewartha, G.,Walker, M.T.,Woolford, A.J. (deposition date: 2008-05-15, release date: 2008-08-05, Last modification date: 2024-05-01)

Primary citation

Wyatt, P.G.,Woodhead, A.J.,Berdini, V.,Boulstridge, J.A.,Carr, M.G.,Cross, D.M.,Davis, D.J.,Devine, L.A.,Early, T.R.,Feltell, R.E.,Lewis, E.J.,Mcmenamin, R.L.,Navarro, E.F.,O'Brien, M.A.,O'Reilly, M.,Reule, M.,Saxty, G.,Seavers, L.C.A.,Smith, D.,Squires, M.S.,Trewartha, G.,Walker, M.T.,Woolford, A.J.
Identification of N-(4-Piperidinyl)-4-(2,6-Dichlorobenzoylamino)-1H-Pyrazole-3-Carboxamide (at7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design.
J.Med.Chem., 51:4986-, 2008

PubMed Abstract: The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.

PubMed: 18656911
DOI: 10.1021/JM800382H

Experimental method

X-RAY DIFFRACTION (2.2 Å)