Discovery of MK-4688: an Efficient Inhibitor of the HDM2?p53 Protein?Protein Interaction

Reutershan, Michael H.; Machacek, Michelle R.; Altman, Michael D.; Bogen, Stephane; Cai, Mingmei; Cammarano, Carolyn; Chen, Dapeng; Christopher, Matthew; Cryan, John; Daublain, Pierre; Fradera, Xavier; Geda, Prasanthi; Goldenblatt, Peter; Hill, Armetta D.; Kemper, Raymond A.; Kutilek, Victoria; Li, Chaomin; Martinez, Michelle; McCoy, Mark; Nair, Latha; Pan, Weidong; Thompson, Christopher F.; Scapin, Giovanna; Shizuka, Manami; Spatz, Marianne L.; Steinhuebel, Dietrich; Sun, Binyuan; Voss, Matthew E.; Wang, Xiao; Yang, Liping; Yeh, Tammie C.; Dussault, Isabelle; Marshall, C. Gary; Trotter, B. Wesley

doi:10.1021/acs.jmedchem.1c01524

Discovery of MK-4688: an Efficient Inhibitor of the HDM2?p53 Protein?Protein Interaction

Journal Article · 01 October 2021 · J. Med. Chem.

DOI:https://doi.org/10.1021/acs.jmedchem.1c01524· OSTI ID:1844722

Reutershan, Michael H.; Machacek, Michelle R.; Altman, Michael D.; Bogen, Stephane; Cai, Mingmei; Cammarano, Carolyn; Chen, Dapeng; Christopher, Matthew; Cryan, John; Daublain, Pierre; Fradera, Xavier; Geda, Prasanthi; Goldenblatt, Peter; Hill, Armetta D.; Kemper, Raymond A.; Kutilek, Victoria; Li, Chaomin; Martinez, Michelle; McCoy, Mark; Nair, Latha more »

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: DOE - Office Of Science; INDUSTRY

OSTI ID:: 1844722

Journal Information:: J. Med. Chem., Vol. 64, Issue (21)

Country of Publication:: United States

Language:: ENGLISH

References (50)

p53, guardian of the genome No authors listed Nature https://doi.org/10.1038/358015a0		July 1992
Surfing the p53 network No authors listed Nature https://doi.org/10.1038/35042675		November 2000
p53: Twenty five years understanding the mechanism of genome protection No authors listed Journal of Physiology and Biochemistry https://doi.org/10.1007/bf03167075		December 2004
The genetics of the p53 pathway, apoptosis and cancer therapy No authors listed Nature Reviews Drug Discovery https://doi.org/10.1038/nrd2656		December 2008
Putting p53 in Context No authors listed Cell https://doi.org/10.1016/j.cell.2017.08.028		September 2017
Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53 No authors listed Nature https://doi.org/10.1038/362857a0		April 1993
Mdm2 promotes the rapid degradation of p53 No authors listed Nature https://doi.org/10.1038/387296a0		May 1997
Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein No authors listed The EMBO Journal https://doi.org/10.1093/emboj/17.2.554		January 1998
The p53 orchestra: Mdm2 and Mdmx set the tone No authors listed Trends in Cell Biology https://doi.org/10.1016/j.tcb.2010.01.009		May 2010
The MDM2 gene amplification database No authors listed Nucleic Acids Research https://doi.org/10.1093/nar/26.15.3453		August 1998
Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients No authors listed Nature Medicine https://doi.org/10.1038/nm.4333		May 2017
Mutational landscape and significance across 12 major cancer types No authors listed Nature https://doi.org/10.1038/nature12634		October 2013
Awakening guardian angels: drugging the p53 pathway No authors listed Nature Reviews Cancer https://doi.org/10.1038/nrc2763		December 2009
Inhibiting the p53–MDM2 interaction: an important target for cancer therapy No authors listed Nature Reviews Cancer https://doi.org/10.1038/nrc991		February 2003
Targeting the p53–MDM2 interaction to treat cancer No authors listed British Journal of Cancer https://doi.org/10.1038/sj.bjc.6602164		September 2004
A role for surface hydrophobicity in protein-protein recognition: Using surface hydrophobicity to locate ligand attachment sites No authors listed Protein Science https://doi.org/10.1002/pro.5560030501		May 1994
Reaching for high-hanging fruit in drug discovery at protein–protein interfaces No authors listed Nature https://doi.org/10.1038/nature06526		December 2007
Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality No authors listed Chemistry & Biology https://doi.org/10.1016/j.chembiol.2014.09.001		September 2014
A Comparison of Physiochemical Property Profiles of Development and Marketed Oral Drugs No authors listed Journal of Medicinal Chemistry https://doi.org/10.1021/jm021053p		March 2003
Design, Synthesis, and Structure–Activity Relationships of Indoline-Based Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-Like 2 (Keap1-Nrf2) Protein–Protein Interaction Inhibitors No authors listed Journal of Medicinal Chemistry https://doi.org/10.1021/acs.jmedchem.0c01116		September 2020
Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction No authors listed Journal of Medicinal Chemistry https://doi.org/10.1021/acs.jmedchem.1c00742		August 2021
Selective Inhibition of Lysine-Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple-Negative Breast Cancer Therapy No authors listed Angewandte Chemie International Edition https://doi.org/10.1002/anie.201807305		July 2018
Enhanced Suppression of a Protein–Protein Interaction in Cells Using Small-Molecule Covalent Inhibitors Based on an N -Acyl- N -alkyl Sulfonamide Warhead No authors listed Journal of the American Chemical Society https://doi.org/10.1021/jacs.1c00703		March 2021
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain No authors listed Science https://doi.org/10.1126/science.274.5289.948		November 1996
Discovery of Potent Antagonists of the Interaction between Human Double Minute 2 and Tumor Suppressor p53 No authors listed Journal of Medicinal Chemistry https://doi.org/10.1021/jm990966p		August 2000
Targeting the MDM2–p53 Protein–Protein Interaction for New Cancer Therapy: Progress and Challenges No authors listed Cold Spring Harbor Perspectives in Medicine https://doi.org/10.1101/cshperspect.a026245		March 2017
Drugging the p53 pathway: understanding the route to clinical efficacy No authors listed Nature Reviews Drug Discovery https://doi.org/10.1038/nrd4236		February 2014
P53 Mdm2 Inhibitors No authors listed Current Pharmaceutical Design https://doi.org/10.2174/138161212802651580		August 2012
Reviving the guardian of the genome: Small molecule activators of p53 No authors listed Pharmacology & Therapeutics https://doi.org/10.1016/j.pharmthera.2017.03.013		October 2017
Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia No authors listed Clinical Cancer Research https://doi.org/10.1158/1078-0432.ccr-15-0481		October 2015
Small-molecule modulation of p53 protein-protein interactions No authors listed Biological Chemistry https://doi.org/10.1515/hsz-2019-0405		July 2020
MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer No authors listed Journal of Hematology & Oncology https://doi.org/10.1186/s13045-017-0500-5		July 2017
Small-Molecule Inhibitors of the MDM2–p53 Protein–Protein Interaction (MDM2 Inhibitors) in Clinical Trials for Cancer Treatment: Miniperspective No authors listed Journal of Medicinal Chemistry https://doi.org/10.1021/jm501092z		November 2014
Phase I Trial of the Human Double Minute 2 Inhibitor MK-8242 in Patients With Advanced Solid Tumors No authors listed Journal of Clinical Oncology https://doi.org/10.1200/jco.2016.70.7117		April 2017
A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML) No authors listed Leukemia Research https://doi.org/10.1016/j.leukres.2016.07.004		September 2016
Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development No authors listed ACS Medicinal Chemistry Letters https://doi.org/10.1021/ml4000657		April 2013
Discovery of RG7388, a Potent and Selective p53–MDM2 Inhibitor in Clinical Development No authors listed Journal of Medicinal Chemistry https://doi.org/10.1021/jm400487c		July 2013
Preclinical Optimization of MDM2 Antagonist Scheduling for Cancer Treatment by Using a Model-Based Approach No authors listed Clinical Cancer Research https://doi.org/10.1158/1078-0432.ccr-14-0460		May 2014
Discovery of a Small Molecule MDM2 Inhibitor (AMG 232) for Treating Cancer No authors listed Journal of Medicinal Chemistry https://doi.org/10.1021/jm500627s		July 2014
The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents No authors listed Molecular Cancer Therapeutics https://doi.org/10.1158/1535-7163.mct-14-0710		January 2015
Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia No authors listed Blood Advances https://doi.org/10.1182/bloodadvances.2019030916		June 2019
Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma No authors listed Investigational New Drugs https://doi.org/10.1007/s10637-019-00840-1		July 2019
A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist, in patients with solid tumours No authors listed European Journal of Cancer https://doi.org/10.1016/j.ejca.2017.02.005		May 2017
A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours No authors listed British Journal of Cancer https://doi.org/10.1038/s41416-018-0355-8		December 2018
Ligand efficiency indices for effective drug discovery No authors listed Expert Opinion on Drug Discovery https://doi.org/10.1517/17460441.2.4.469		April 2007
Functional group contributions to drug-receptor interactions No authors listed Journal of Medicinal Chemistry https://doi.org/10.1021/jm00378a021		December 1984
The influence of drug-like concepts on decision-making in medicinal chemistry No authors listed Nature Reviews Drug Discovery https://doi.org/10.1038/nrd2445		November 2007
The role of ligand efficiency metrics in drug discovery No authors listed Nature Reviews Drug Discovery https://doi.org/10.1038/nrd4163		January 2014
Fluorescence polarization assay and inhibitor design for MDM2/p53 interaction No authors listed Analytical Biochemistry https://doi.org/10.1016/s0003-2697(04)00223-4		August 2004
Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors No authors listed ACS Medicinal Chemistry Letters https://doi.org/10.1021/acsmedchemlett.5b00472		January 2016

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