title: Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design.
abstract: Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been validated as an attractive therapeutic target for cancer therapy. To stop both STAT3 activation and dimerization, a viable strategy is to design inhibitors blocking its SH2 domain phosphotyrosine binding site that is responsible for both actions. A new fragment-based drug design (FBDD) strategy, in silico site-directed FBDD, was applied in this study. A designed novel compound, 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY5), was confirmed to bind to STAT3 SH2 by fluorescence polarization assay. In addition, four out of the five chosen compounds have IC50 values lower than 5 μM for the U2OS cancer cells. 8 (LY5) has an IC50 range in 0.5-1.4 μM in various cancer cell lines. 8 also suppresses tumor growth in an in vivo mouse model. This study has demonstrated the utility of this approach and could be used to other drug targets in general.
authors: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
authors: Wenying
authors: W
authors: Yu
authors: Hui
authors: H
authors: Xiao
authors: Jiayuh
authors: J
authors: Lin
authors: Chenglong
authors: C
authors: Li
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005454:Fluorescence Polarization; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects; D018909:src Homology Domains
chemical_list: C582914:5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide; D000631:Aminopyridines; D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D054852:Small Molecule Libraries; D013449:Sulfonamides