Identification of a disruptor of the MDM2-p53 protein-protein interaction facilitated by high-throughput in silico docking.
NSC 333003 has been identified from the NCI Diversity Set as an inhibitor of the MDM2-p53 protein-protein interaction by in silico docking (virtual screening). Its potency and chemical characteristics render it well suited for lead optimization studies that can result in more potent analogs with improved drug-like properties. Its synthesis was achieved using an acid catalyzed condensation reaction from commercially available benzothiazole hydrazine and pyridyl phenyl ketone in refluxing methanol. Stereochemical implications for this compound are described.
Lawrence
Harshani R
HR
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Li
Zhenyu
Z
Yip
M L Richard
ML
Sung
Shen-Shu
SS
Lawrence
Nicholas J
NJ
McLaughlin
Mark L
ML
McManus
Gregory J
GJ
Zaworotko
Michael J
MJ
Sebti
Saïd M
SM
Chen
Jiandong
J
Guida
Wayne C
WC
D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D054730:Protein Interaction Domains and Motifs; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism
D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D006834:Hydrazines; C544463:NSC 333003; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2