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Literature DB >> 25147610

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction.

Ming Yu¹, Yingcai Wang¹, Jiang Zhu¹, Michael D Bartberger², Jude Canon², Ada Chen¹, David Chow¹, John Eksterowicz¹, Brian Fox¹, Jiasheng Fu¹, Michael Gribble¹, Xin Huang³, Zhihong Li¹, Jiwen Jim Liu¹, Mei-Chu Lo¹, Dustin McMinn¹, Jonathan D Oliner², Tao Osgood², Yosup Rew¹, Anne Y Saiki², Paul Shaffer³, Xuelei Yan¹, Qiuping Ye¹, Dongyin Yu², Xiaoning Zhao¹, Jing Zhou¹, Steven H Olson¹, Julio C Medina¹, Daqing Sun¹.

Abstract

Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model.

Entities: Chemical Disease Gene Species

Keywords: MDM2; p53; piperidinone; protein−protein interaction; pyridine

Year: 2014 PMID： 25147610 PMCID： PMC4137378 DOI： 10.1021/ml500142b

Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345

13 in total

Review 1. p53 and human cancer: the first ten thousand mutations.

Authors: P Hainaut; M Hollstein
Journal: Adv Cancer Res Date: 2000 Impact factor: 6.242

2. Structure-based design of novel inhibitors of the MDM2-p53 interaction.

Authors: Yosup Rew; Daqing Sun; Felix Gonzalez-Lopez De Turiso; Michael D Bartberger; Hilary P Beck; Jude Canon; Ada Chen; David Chow; Jeffrey Deignan; Brian M Fox; Darin Gustin; Xin Huang; Min Jiang; Xianyun Jiao; Lixia Jin; Frank Kayser; David J Kopecky; Yihong Li; Mei-Chu Lo; Alexander M Long; Klaus Michelsen; Jonathan D Oliner; Tao Osgood; Mark Ragains; Anne Y Saiki; Steve Schneider; Maria Toteva; Peter Yakowec; Xuelei Yan; Qiuping Ye; Dongyin Yu; Xiaoning Zhao; Jing Zhou; Julio C Medina; Steven H Olson
Journal: J Med Chem Date: 2012-05-09 Impact factor: 7.446

3. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development.

Authors: Qingjie Ding; Zhuming Zhang; Jin-Jun Liu; Nan Jiang; Jing Zhang; Tina M Ross; Xin-Jie Chu; David Bartkovitz; Frank Podlaski; Cheryl Janson; Christian Tovar; Zoran M Filipovic; Brian Higgins; Kelli Glenn; Kathryn Packman; Lyubomir T Vassilev; Bradford Graves
Journal: J Med Chem Date: 2013-07-16 Impact factor: 7.446

4. Inhibitors of the p53/hdm2 protein-protein interaction-path to the clinic.

Authors: Jean-Christophe Carry; Carlos Garcia-Echeverria
Journal: Bioorg Med Chem Lett Date: 2013-03-16 Impact factor: 2.823

5. mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein.

Authors: J Chen; X Wu; J Lin; A J Levine
Journal: Mol Cell Biol Date: 1996-05 Impact factor: 4.272

6. Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development.

Authors: Binh Vu; Peter Wovkulich; Giacomo Pizzolato; Allen Lovey; Qingjie Ding; Nan Jiang; Jin-Jun Liu; Chunlin Zhao; Kelli Glenn; Yang Wen; Christian Tovar; Kathryn Packman; Lyubomir Vassilev; Bradford Graves
Journal: ACS Med Chem Lett Date: 2013-04-02 Impact factor: 4.345

7. Amplification of a gene encoding a p53-associated protein in human sarcomas.

Authors: J D Oliner; K W Kinzler; P S Meltzer; D L George; B Vogelstein
Journal: Nature Date: 1992-07-02 Impact factor: 49.962

Review 8. The genetics of the p53 pathway, apoptosis and cancer therapy.

Authors: Alexei Vazquez; Elisabeth E Bond; Arnold J Levine; Gareth L Bond
Journal: Nat Rev Drug Discov Date: 2008-12 Impact factor: 84.694

Review 9. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy.

Authors: Patrick Chène
Journal: Nat Rev Cancer Date: 2003-02 Impact factor: 60.716

10. A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice.

Authors: Yujun Zhao; Shanghai Yu; Wei Sun; Liu Liu; Jianfeng Lu; Donna McEachern; Sanjeev Shargary; Denzil Bernard; Xiaoqin Li; Ting Zhao; Peng Zou; Duxin Sun; Shaomeng Wang
Journal: J Med Chem Date: 2013-06-20 Impact factor: 7.446

7 in total

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction.

Review 1. p53 and human cancer: the first ten thousand mutations.

2. Structure-based design of novel inhibitors of the MDM2-p53 interaction.

3. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development.

4. Inhibitors of the p53/hdm2 protein-protein interaction-path to the clinic.

5. mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein.

6. Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development.

7. Amplification of a gene encoding a p53-associated protein in human sarcomas.

Review 8. The genetics of the p53 pathway, apoptosis and cancer therapy.

Review 9. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy.

10. A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice.

Review 1. Reviving the guardian of the genome: Small molecule activators of p53.

Review 2. Targeting p53-MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials.

3. New Frontiers in Druggability.

4. iPPI-DB: an online database of modulators of protein-protein interactions.

5. Identification of new inhibitors of Mdm2-p53 interaction via pharmacophore and structure-based virtual screening.

Review 6. Recent Synthetic Approaches towards Small Molecule Reactivators of p53.

Review 7. Chemical Variations on the p53 Reactivation Theme.