Potent and Orally Active Small-Molecule Inhibitors of the MDM2-p53 Interaction

被引：161

作者：

Yu, Shanghai ^{[1
,2
,3
,4
]}

Qin, Dongguang ^{[1
,2
,3
,4
]}

Shangary, Sanjeev ^{[1
,2
,3
,4
]}

Chen, Jianyong ^{[1
,2
,3
,4
]}

Wang, Guoping ^{[1
,2
,3
,4
]}

Ding, Ke ^{[1
,2
,3
,4
]}

McEachern, Donna ^{[1
,2
,3
,4
]}

Qiu, Su ^{[1
,2
,3
,4
]}

Nikolovska-Coleska, Zaneta ^{[1
,2
,3
,4
]}

Miller, Rebecca ^{[1
,2
,3
,4
]}

Kang, Sanmao ^{[5
]}

Yang, Dajun ^{[5
]}

Wang, Shaomeng ^{[1
,2
,3
,4
]}

机构：

[1] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

[5] Ascenta Therapeut Inc, Malvern, PA 19355 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 24期

基金：

美国国家卫生研究院;

关键词：

PROTEIN-PROTEIN INTERACTION; STRUCTURE-BASED DESIGN; CANCER-THERAPY; P53-MDM2; INTERACTION; P53; ANTAGONISTS; ACTIVATION; DISCOVERY; CELLS; GROWTH;

D O I：

10.1021/jm901400z

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction, Compound 5 binds to MDM2 with a K-i of 0.6 nM, activates p53 at concentrations its low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.

引用

收藏

页码：7970 / 7973

页数：4

相关论文

共 22 条

[1] Small molecule inhibitors of the MDM2-p53 interaction discovered by ensemble-based receptor models [J].

Bowman, Anna L. ;

Nikolovska-Coleska, Zaneta ;

Zhong, Haizhen ;

Wang, Shaomeng ;

Carlson, Heather A. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2007, 129 (42) :12809-12814

[2] Inhibiting the p53-MDM2 interaction:: An important target for cancer therapy [J].

Chène, P .

NATURE REVIEWS CANCER, 2003, 3 (02) :102-109

[3] Structure-based design of potent non-peptide MDM2 inhibitors [J].

Ding, K ;

Lu, Y ;

Nikolovska-Coleska, Z ;

Qiu, S ;

Ding, YS ;

Gao, W ;

Stuckey, J ;

Krajewski, K ;

Roller, PP ;

Tomita, Y ;

Parrish, DA ;

Deschamps, JR ;

Wang, SM .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2005, 127 (29) :10130-10131

[4] Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction [J].

Ding, Ke ;

Lu, Yipin ;

Nikolovska-Coleska, Zaneta ;

Wang, Guoping ;

Qiu, Su ;

Shangary, Sanjeev ;

Gao, Wei ;

Qin, Dongguang ;

Stuckey, Jeanne ;

Krajewski, Krzysztof ;

Roller, Peter P. ;

Wang, Shaomeng .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (12) :3432-3435

[5] A nonpeptidic sulfonamide inhibits the p53-mdm2 interaction and activates p53-dependent transcription in mdm2-overexpressing cells [J].

Galatin, PS ;

Abraham, DJ .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (17) :4163-4165

[6] Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53 [J].

García-Echeverría, C ;

Chène, P ;

Blommers, MJJ ;

Furet, P .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (17) :3205-3208

[7] Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells [J].

Grasberger, BL ;

Lu, TB ;

Schubert, C ;

Parks, DJ ;

Carver, TE ;

Koblish, HK ;

Cummings, MD ;

LaFrance, LV ;

Milkiewicz, KL ;

Calvo, RR ;

Maguire, D ;

Lattanze, J ;

Franks, CF ;

Zhao, SY ;

Ramachandren, K ;

Bylebyl, GR ;

Zhang, M ;

Manthey, CL ;

Petrella, EC ;

Pantoliano, MW ;

Deckman, IC ;

Spurlino, JC ;

Maroney, AC ;

Tomczuk, BE ;

Molloy, CJ ;

Bone, RF .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (04) :909-912

[8] Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold [J].

Hardcastle, Ian R. ;

Ahmed, Shafiq U. ;

Atkins, Helen ;

Farnie, Gillian ;

Golding, Bernard T. ;

Griffin, Roger J. ;

Guyenne, Sabrina ;

Hutton, Claire ;

Kallblad, Per ;

Kemp, Stuart J. ;

Kitching, Martin S. ;

Newell, David R. ;

Norbedo, Stefano ;

Northen, Julian S. ;

Reid, Rebecca J. ;

Saravanan, K. ;

Willems, Henriette M. G. ;

Lunec, John .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (21) :6209-6221

[9] Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain [J].

Kussie, PH ;

Gorina, S ;

Marechal, V ;

Elenbaas, B ;

Moreau, J ;

Levine, AJ ;

Pavletich, NP .

SCIENCE, 1996, 274 (5289) :948-953

[10] p53, the cellular gatekeeper for growth and division [J].

Levine, AJ .

CELL, 1997, 88 (03) :323-331