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Literature DB >> 26181851

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors.

Philipp Holzer¹, Keiichi Masuya¹, Pascal Furet¹, Joerg Kallen¹, Therese Valat-Stachyra¹, Stéphane Ferretti¹, Joerg Berghausen¹, Michèle Bouisset-Leonard¹, Nicole Buschmann¹, Carole Pissot-Soldermann¹, Caroline Rynn¹, Stephan Ruetz¹, Stefan Stutz¹, Patrick Chène¹, Sébastien Jeay¹, Francois Gessier¹.

Abstract

As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.

Entities: Chemical Disease Gene

Mesh：

Substances：

Year: 2015 PMID： 26181851 DOI： 10.1021/acs.jmedchem.5b00810

Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446

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Cited

51 in total

1. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf^-/- mouse model.

Authors: Emilie A Chapeau; Agnieszka Gembarska; Eric Y Durand; Emeline Mandon; Claire Estadieu; Vincent Romanet; Marion Wiesmann; Ralph Tiedt; Joseph Lehar; Antoine de Weck; Roland Rad; Louise Barys; Sebastien Jeay; Stephane Ferretti; Audrey Kauffmann; Esther Sutter; Armelle Grevot; Pierre Moulin; Masato Murakami; William R Sellers; Francesco Hofmann; Michael Rugaard Jensen
Journal: Proc Natl Acad Sci U S A Date: 2017-03-06 Impact factor: 11.205

2. Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression.

Authors: Yangbing Li; Jiuling Yang; Angelo Aguilar; Donna McEachern; Sally Przybranowski; Liu Liu; Chao-Yie Yang; Mi Wang; Xin Han; Shaomeng Wang
Journal: J Med Chem Date: 2018-12-10 Impact factor: 7.446

3. A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma.

Authors: Clemens Krepler; Katrin Sproesser; Patricia Brafford; Marilda Beqiri; Bradley Garman; Min Xiao; Batool Shannan; Andrea Watters; Michela Perego; Gao Zhang; Adina Vultur; Xiangfan Yin; Qin Liu; Ioannis N Anastopoulos; Bradley Wubbenhorst; Melissa A Wilson; Wei Xu; Giorgos Karakousis; Michael Feldman; Xiaowei Xu; Ravi Amaravadi; Tara C Gangadhar; David E Elder; Lauren E Haydu; Jennifer A Wargo; Michael A Davies; Yiling Lu; Gordon B Mills; Dennie T Frederick; Michal Barzily-Rokni; Keith T Flaherty; Dave S Hoon; Michael Guarino; Joseph J Bennett; Randall W Ryan; Nicholas J Petrelli; Carol L Shields; Mizue Terai; Takami Sato; Andrew E Aplin; Alexander Roesch; David Darr; Steve Angus; Rakesh Kumar; Ensar Halilovic; Giordano Caponigro; Sebastien Jeay; Jens Wuerthner; Annette Walter; Matthias Ocker; Matthew B Boxer; Lynn Schuchter; Katherine L Nathanson; Meenhard Herlyn
Journal: Cell Rep Date: 2017-11-14 Impact factor: 9.423

Review 4. Reviving the guardian of the genome: Small molecule activators of p53.

Authors: Daniel Nguyen; Wenjuan Liao; Shelya X Zeng; Hua Lu
Journal: Pharmacol Ther Date: 2017-03-27 Impact factor: 12.310

Review 5. Inhibitors of protein-protein interactions (PPIs): an analysis of scaffold choices and buried surface area.

Authors: Xu Ran; Jason E Gestwicki
Journal: Curr Opin Chem Biol Date: 2018-06-13 Impact factor: 8.822

6. Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas.

Authors: Jelena Todoric; Laura Antonucci; Giuseppe Di Caro; Ning Li; Xuefeng Wu; Nikki K Lytle; Debanjan Dhar; Sourav Banerjee; Johan B Fagman; Cecille D Browne; Atsushi Umemura; Mark A Valasek; Hannes Kessler; David Tarin; Michael Goggins; Tannishtha Reya; Maria Diaz-Meco; Jorge Moscat; Michael Karin
Journal: Cancer Cell Date: 2017-11-16 Impact factor: 31.743

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors.

1. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf^-/- mouse model.

2. Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression.

3. A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma.

Review 4. Reviving the guardian of the genome: Small molecule activators of p53.

Review 5. Inhibitors of protein-protein interactions (PPIs): an analysis of scaffold choices and buried surface area.

6. Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas.

Review 7. Targeting MDM2 for novel molecular therapy: Beyond oncology.

Review 8. How To Design a Successful p53-MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures.

Review 9. Ubiquitin-proteasome system-targeted therapy for uveal melanoma: what is the evidence?

Review 10. Decoding the messaging of the ubiquitin system using chemical and protein probes.

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors.

1. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf-/- mouse model.

2. Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression.

3. A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma.

Review 4. Reviving the guardian of the genome: Small molecule activators of p53.

Review 5. Inhibitors of protein-protein interactions (PPIs): an analysis of scaffold choices and buried surface area.

6. Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas.

Review 7. Targeting MDM2 for novel molecular therapy: Beyond oncology.

Review 8. How To Design a Successful p53-MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures.

Review 9. Ubiquitin-proteasome system-targeted therapy for uveal melanoma: what is the evidence?

Review 10. Decoding the messaging of the ubiquitin system using chemical and protein probes.

1. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf^-/- mouse model.