Discovery of Potent and Selective p53-MDM2 Protein-Protein Interaction Inhibitors as Anticancer Drugs

被引：18

作者：

Holzer, Philipp ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland

来源：

CHIMIA | 2017年 / 71卷 / 10期

关键词：

Clinical trial; HDM2; Inhibitor; MDM2; NVP-CGM097; NVP-HDM201; p53; Protein-protein interaction; PPI; STRUCTURE-BASED DESIGN; P53; PATHWAY; MDM2-P53; INTERACTION; HIGHLY POTENT; ANTAGONISTS; CANCER; TUMORS;

D O I：

10.2533/chimia.2017.716

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

As a result of our persistent efforts to discover novel inhibitors of the p53-MDM2 protein-protein interaction useful for the treatment of cancer, the potent and selective MDM2 inhibitors NVP-CGM097 and NVP-HDM201 with excellent in vitro and in vivo profile were selected as clinical candidates and are currently in phase 1 clinical development. This short review article provides a summary of the program history, the applied pharmacophore model and the discovery story of these novel p53-MDM2 inhibitor investigational drugs.

引用

页码：716 / 721

页数：6

共 28 条

[1]

DiNardo C. D., 2016, 58 ANN M EXP SAN DIE

[2] Discovery of RG7388, a Potent and Selective p53-MDM2 Inhibitor in Clinical Development [J].

Ding, Qingjie ;

Zhang, Zhuming ;

Liu, Jin-Jun ;

Jiang, Nan ;

Zhang, Jing ;

Ross, Tina M. ;

Chu, Xin-Jie ;

Bartkovitz, David ;

Podlaski, Frank ;

Janson, Cheryl ;

Tovar, Christian ;

Filipovic, Zoran M. ;

Higgins, Brian ;

Glenn, Kelli ;

Packman, Kathryn ;

Vassilev, Lyubomir T. ;

Graves, Bradford .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (14) :5979-5983

[3] Mutational spectrum of p53 mutations in primary breast and ovarian tumors [J].

Feki, A ;

Irminger-Finger, I .

CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, 2004, 52 (02) :103-116

[4] Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument [J].

Furet, Pascal ;

Masuya, Keiichi ;

Kallen, Joerg ;

Stachyra-Valat, Therese ;

Ruetz, Stephan ;

Guagnano, Vito ;

Holzer, Philipp ;

Mah, Robert ;

Stutz, Stefan ;

Vaupel, Andrea ;

Chene, Patrick ;

Jeay, Sebastien ;

Schlapbach, Achim .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (19) :4837-4841

[5] The central valine concept provides an entry in a new class of non peptide inhibitors of the p53-MDM2 interaction [J].

Furet, Pascal ;

Chene, Patrick ;

De Pover, Alain ;

Valat, Therese Stachyra ;

Lisztwan, Joanna Hergovich ;

Kallen, Joerg ;

Masuya, Keiichi .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (10) :3498-3502

[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] Targeting Protein-Protein Interactions to Treat Cancer-Recent Progress and Future Directions [J].

Garland, William ;

Benezra, Robert ;

Chaudhary, Jaideep .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 48, 2013, 48 :227-245

[8] Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode [J].

Gessier, Francois ;

Kallen, Joerg ;

Jacoby, Edgar ;

Chene, Patrick ;

Stachyra-Valat, Therese ;

Ruetz, Stephan ;

Jeay, Sebastien ;

Holzer, Philipp ;

Masuya, Keiichi ;

Furet, Pascal .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (17) :3621-3625

[9] The p53 pathway: positive and negative feedback loops [J].

Harris, SL ;

Levine, AJ .

ONCOGENE, 2005, 24 (17) :2899-2908

[10] Drugging the p53 pathway: understanding the route to clinical efficacy [J].

Hoe, Khoo Kian ;

Verma, Chandra S. ;

Lane, David P. .

NATURE REVIEWS DRUG DISCOVERY, 2014, 13 (03) :217-236

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