Structure-Based Design of Novel Inhibitors of the MDM2-p53 Interaction

被引：135

作者：

Rew, Yosup ^{[1
]}

Sun, Daqing ^{[1
]}

De Turiso, Felix Gonzalez-Lopez ^{[1
]}

Bartberger, Michael D. ^{[4
]}

Beck, Hilary P. ^{[1
]}

Canon, Jude ^{[5
]}

Chen, Ada ^{[1
]}

Chow, David ^{[1
]}

Deignan, Jeffrey ^{[1
]}

Fox, Brian M. ^{[1
]}

Gustin, Darin ^{[1
]}

Huang, Xin ^{[6
]}

Jiang, Min ^{[3
]}

Jiao, Xianyun ^{[1
]}

Jin, Lixia ^{[3
]}

Kayser, Frank ^{[1
]}

Kopecky, David J. ^{[1
]}

Li, Yihong ^{[1
]}

Lo, Mei-Chu ^{[1
]}

Long, Alexander M. ^{[6
]}

Michelsen, Klaus ^{[4
]}

Oliner, Jonathan D. ^{[5
]}

Osgood, Tao ^{[5
]}

Ragains, Mark ^{[2
]}

Saiki, Anne Y. ^{[5
]}

Schneider, Steve ^{[6
]}

Toteva, Maria ^{[2
]}

Yakowec, Peter ^{[6
]}

Yan, Xuelei ^{[1
]}

Ye, Qiuping ^{[3
]}

Yu, Dongyin ^{[5
]}

Zhao, Xiaoning ^{[1
]}

Zhou, Jing ^{[1
]}

Medina, Julio C. ^{[1
]}

Olson, Steven H. ^{[1
]}

机构：

[1] Amgen Inc, Dept Therapeut Discovery, San Francisco, CA 94080 USA

[2] Amgen Inc, Dept Pharmaceut, San Francisco, CA 94080 USA

[3] Amgen Inc, Dept Pharmacokinet & Drug Metab, San Francisco, CA 94080 USA

[4] Amgen Inc, Dept Therapeut Discovery, Thousand Oaks, CA 91320 USA

[5] Amgen Inc, Dept Oncol Res, Thousand Oaks, CA 91320 USA

[6] Amgen Inc, Dept Therapeut Discovery, Cambridge, MA 02142 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 11期

关键词：

P53; RESTORATION; CANCER-THERAPY; IN-VIVO; ACTIVATION; APOPTOSIS; TUMORS; MOLECULES; PATHWAY; LEADS; P21;

D O I：

10.1021/jm300354j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.

引用

页码：4936 / 4954

页数：19

共 23 条

[1] Discovery and Optimization of Chromenotriazolopyrimidines as Potent Inhibitors of the Mouse Double Minute 2-Tumor Protein 53 Protein-Protein Interaction
Allen, John G.
Bourbeau, Matthew P.
Wohlhieter, G. Erich
Bartberger, Michael D.
Michelsen, Klaus
Hungate, Randall
Gadwood, Robert C.
Gaston, Rick D.
Evans, Bruce
Mann, Larry W.
Matison, Michael E.
Schneider, Stephen
Huang, Xin
Yu, Dongyin
Andrews, Paul S.
Reichelt, Andreas
Long, Alexander M.
Yakowec, Peter
Yang, Evelyn Y.
Lee, Tani Ann
Oliner, Jonathan D.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (22) : 7044 - 7053
[2] Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream
Arkin, MR
Wells, JA
[J]. NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (04) : 301 - 317
[3] Improvement of the synthesis and pharmacokinetic properties of chromenotriazolopyrimidine MDM2-p53 protein-protein inhibitors
Beck, Hilary P.
DeGraffenreid, Michael
Fox, Brian
Allen, John G.
Rew, Yosup
Schneider, Stephen
Saiki, Anne Y.
Yu, Dongyin
Oliner, Jonathan D.
Salyers, Kevin
Ye, Qiuping
Olson, Steven
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (09) : 2752 - 2755
[4] Requirement for p53 and p21 to sustain G2 arrest after DNA damage
Bunz, F
Dutriaux, A
Lengauer, C
Waldman, T
Zhou, S
Brown, JP
Sedivy, JM
Kinzler, KW
Vogelstein, B
[J]. SCIENCE, 1998, 282 (5393) : 1497 - 1501
[5] CASE DA, 2006, AMBER VERSION 9
[6] Inhibiting the p53-MDM2 interaction:: An important target for cancer therapy
Chène, P
[J]. NATURE REVIEWS CANCER, 2003, 3 (02) : 102 - 109
[7] FLAME: A program to flexibly align molecules
Cho, SJ
Sun, YX
[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2006, 46 (01) : 298 - 306
[8] WAF1, A POTENTIAL MEDIATOR OF P53 TUMOR SUPPRESSION
ELDEIRY, WS
TOKINO, T
VELCULESCU, VE
LEVY, DB
PARSONS, R
TRENT, JM
LIN, D
MERCER, WE
KINZLER, KW
VOGELSTEIN, B
[J]. CELL, 1993, 75 (04) : 817 - 825
[9] Elliott J.D., 1998, Patent US, Patent No. [5817653 A1, 5817653]
[10] Pivotal role of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in apoptosis and autophagy
Fujiwara, Keishi
Daido, Shigeru
Yamamoto, Akitsugu
Kobayashi, Ryuji
Yokoyama, Tomohisa
Aoki, Hiroshi
Iwado, Eiji
Shinojima, Naoki
Kondo, Yasuko
Kondo, Seiji
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (01) : 388 - 397

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