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

被引：312

作者：

Wyatt, Paul G. ^{[1
]}

Woodhead, Andrew J. ^{[1
]}

Berdini, Valerio ^{[4
]}

Boulstridge, John A. ^{[1
]}

Carr, Maria G. ^{[1
]}

Cross, David M. ^{[5
]}

Davis, Deborah J. ^{[3
]}

Devine, Lindsay A. ^{[2
]}

Early, Theresa R. ^{[1
]}

Feltell, Ruth E. ^{[3
]}

Lewis, E. Jonathan ^{[5
]}

McMenamin, Rachel L. ^{[3
]}

Navarro, Eva F. ^{[1
]}

O'Brien, Michael A. ^{[1
]}

O'Reilly, Marc ^{[2
]}

Reule, Matthias ^{[5
]}

Saxty, Gordon ^{[1
]}

Seavers, Lisa C. A. ^{[3
]}

Smith, Donna-Michelle ^{[5
]}

Squires, Matt S. ^{[3
]}

Trewartha, Gary ^{[1
]}

Walker, Margaret T. ^{[1
]}

Woolford, Alison J. -A. ^{[1
]}

机构：

[1] Astex Therapeut Ltd, Med Chem, Cambridge CB4 0QA, England

[2] Astex Therapeut Ltd, Struct Biol, Cambridge CB4 0QA, England

[3] Astex Therapeut Ltd, Biol, Cambridge CB4 0QA, England

[4] Astex Therapeut Ltd, Computat Chem & Informat, Cambridge CB4 0QA, England

[5] Astex Therapeut Ltd, DMPK, Cambridge CB4 0QA, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 16期

关键词：

D O I：

10.1021/jm800382h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：4986 / 4999

页数：14

共 52 条

[41] Involvement of Myc activity in a G1/S-promoting mechanism parallel to the pRb/E2F pathway [J].

Santoni-Rugiu, E ;

Falck, J ;

Mailand, N ;

Bartek, J ;

Lukas, J .

MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (10) :3497-3509

[42] High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: Bound waters and natural ligand as guides for inhibitor design [J].

SchulzeGahmen, U ;

DeBondt, HL ;

Kim, SH .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (23) :4540-4546

[43] Inhibitors of cyclin dependent kinases: Useful targets for cancer treatment [J].

Sharma, P. Sapra ;

Sharma, R. ;

Tyagi, R. .

CURRENT CANCER DRUG TARGETS, 2008, 8 (01) :53-75

[44] Cancer cell cycles [J].

Sherr, CJ .

SCIENCE, 1996, 274 (5293) :1672-1677

[45] Proliferation of cancer cells despite CDK2 inhibition [J].

Tetsu, O ;

McCormick, F .

CANCER CELL, 2003, 3 (03) :233-245

[46]

Tisi D, 2008, CANCER DRUG DESIGN AND DISCOVERY, P91, DOI 10.1016/B978-012369448-5.50007-0

[47] Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6 [J].

Toogood, PL ;

Harvey, PJ ;

Repine, JT ;

Sheehan, DJ ;

VanderWel, SN ;

Zhou, HR ;

Keller, PR ;

McNamara, DJ ;

Sherry, D ;

Zhu, T ;

Brodfuehrer, J ;

Choi, C ;

Barvian, MR ;

Fry, DW .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (07) :2388-2406

[48]

*US FDA, 2007, COMM ORPH MED PROD 8

[49] DISTINCT ROLES FOR CYCLIN-DEPENDENT KINASES IN CELL-CYCLE CONTROL [J].

VANDENHEUVEL, S ;

HARLOW, E .

SCIENCE, 1993, 262 (5142) :2050-2054

[50] THE RETINOBLASTOMA PROTEIN AND CELL-CYCLE CONTROL [J].

WEINBERG, RA .

CELL, 1995, 81 (03) :323-330

← 1 2 3 4 5 6 →