Searching for Dual Inhibitors of the MDM2-p53 and MDMX-p53 Protein-Protein Interaction by a Scaffold-Hopping Approach.
Two libraries of substituted benzimidazoles were designed using a 'scaffold-hopping' approach based on reported MDM2-p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X-ray structure. Benzimidazole libraries were prepared using an efficient solution-phase approach and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions. Key examples showed inhibitory activity against both targets.
Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Newcastle University, Bedson Building, Newcastle upon Tyne, NE1 7RU, UK.
Andrey
A
Zaytsev
Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Newcastle University, Bedson Building, Newcastle upon Tyne, NE1 7RU, UK.
Barry
B
Dodd
Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, Siena, 53100, Italy.
Matteo
M
Magnani
Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, Siena, 53100, Italy.
Chiara
C
Ghiron
Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Newcastle University, Bedson Building, Newcastle upon Tyne, NE1 7RU, UK.
Bernard T
BT
Golding
Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Newcastle University, Bedson Building, Newcastle upon Tyne, NE1 7RU, UK.
Roger J
RJ
Griffin
Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Junfeng
J
Liu
Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Xiaohong
X
Lu
Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, Siena, 53100, Italy.
Iolanda
I
Micco
Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
David R
DR
Newell
Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, Siena, 53100, Italy.
Alessandro
A
Padova
Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, Siena, 53100, Italy.
Graeme
G
Robertson
Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
John
J
Lunec
Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Newcastle University, Bedson Building, Newcastle upon Tyne, NE1 7RU, UK.
Ian R
IR
Hardcastle
D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
drug design; drug discovery; protein-protein interaction; structure-based drug design; virtual screening