title: Fragment-based drug discovery of 2-thiazolidinones as inhibitors of the histone reader BRD4 bromodomain.
abstract: Recognizing acetyllysine of histone is a vital process of epigenetic regulation that is mediated by a protein module called bromodomain. To contribute novel scaffolds for developing into bromodomain inhibitors, we utilize a fragment-based drug discovery approach. By successively applying docking and X-ray crystallography, we were able to identify 9 fragment hits from diffracting more than 60 crystals. In the present work, we described four of them and carried out the integrated lead optimization for fragment 8, which bears a 2-thiazolidinone core. After several rounds of structure guided modifications, we assessed the druggability of 2-thiazolidinone by modulating in vitro pharmacokinetic studies and cellular activity assay. The results showed that two potent compounds of 2-thiazolidinones have good metabolic stability. Also, the cellular assay confirmed the activities of 2-thiazolidinones. Together, we hope the identified 2-thiazolidinone chemotype and other fragment hits described herein can stimulate researchers to develop more diversified bromodomain inhibitors.
authors.affiliation: Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Lele
authors.initials: L
authors.lastname: Zhao
authors.forename: Danyan
authors.initials: D
authors.lastname: Cao
authors.forename: Tiantian
authors.initials: T
authors.lastname: Chen
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Wang
authors.forename: Zehong
authors.initials: Z
authors.lastname: Miao
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Wuyan
authors.initials: W
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Yanlian
authors.initials: Y
authors.lastname: Li
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Du
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Chunyan
authors.initials: C
authors.lastname: Xu
authors.forename: Naixia
authors.initials: N
authors.lastname: Zhang
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D005454:Fluorescence Polarization; D019073:HT29 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D008024:Ligands; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D053778:Thiazolidines; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins