title: Biased multicomponent reactions to develop novel bromodomain inhibitors.
abstract: BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute , 450 Brookline Avenue, Boston, Massachusetts 02215, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: McKeown
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Shaw
authors.forename: Harry
authors.initials: H
authors.lastname: Fu
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.forename: Xiang
authors.initials: X
authors.lastname: Xu
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Marineau
authors.forename: Yibo
authors.initials: Y
authors.lastname: Huang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Buckley
authors.forename: Asha
authors.initials: A
authors.lastname: Kadam
authors.forename: Zijuan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Blacklow
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
mesh_terms: D017738:Alkanesulfonic Acids / Q000737:chemistry; D001381:Azepines / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D005466:Fluorocarbons / Q000737:chemistry; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis; D054852:Small Molecule Libraries / Q000138:chemical synthesis; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000092468:Bromodomain Containing Proteins
chemical_list: D017738:Alkanesulfonic Acids; D001381:Azepines; D018797:Cell Cycle Proteins; D005466:Fluorocarbons; D007093:Imidazoles; D007555:Isoxazoles; D008024:Ligands; D009687:Nuclear Proteins; D011719:Pyrazines; D011725:Pyridines; D054852:Small Molecule Libraries; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000595653:N-(tert-butyl)-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)imidazo(1,2-a)pyrazin-3-amine; C076994:perfluorooctane sulfonic acid