Bronner, SM; Murray, J; Romero, FA; Lai, KW; Tsui, V; Cyr, P; Beresini, MH; De Leon Boenig, G; Chen, Z; Choo, EF; Clark, KR; Crawford, TD; Jayaram, H; Kaufman, S; Li, R; Li, Y; Liao, J; Liang, X; Liu, W; Ly, J; Maher, J; Wai, J; Wang, F; Zheng, A; Zhu, X; Magnuson, S
The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we disclosed the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind the KAc region and then building into the LPF shelf. Herein, we report the "hybridization" of a variety of KAc-binding fragments with a tetrahydroquinoline scaffold that makes optimal interactions with the LPF shelf, imparting enhanced potency and selectivity to the hybridized ligand. To demonstrate the utility of our hybridization approach, two analogues containing unique Asn binders and the optimized tetrahydroquinoline moiety were rapidly optimized to yield single-digit nanomolar inhibitors of CBP with exquisite selectivity over BRD4(1) and the broader bromodomain family. © 2017 American Chemical Society.
1 (6 bromo 3,4 dihydro 2h quinolin 1 yl)ethanone; 1 methyl 5 bromo 1 [[2 (trimethylsilyl)ethoxy]methyl] 1h indole 3 carboxylate; 1 [6 [7 (difluoromethyl) 6 (1 methyl 1h pyrazol 4 yl) 3,4 dihydroquinolin 1(2h) yl] 4 methoxypyridin 2 yl) 3 methylurea; 1 [6 [7 (difluoromethyl) 6 (1 methyl 1h pyrazol 4 yl) 3,4 dihydroquinolin 1(2h) yl] 4 methoxypyridin 2 yl] 3 methylurea; 1 [6 [7 (difluoromethyl) 6 (1 methylpyrazol 4 yl) 3,4 dihydro 2h quinolin 1 yl] 3,4 dihydro 2h quinolin 1 yl]ethanone; 4 [7 (difluoromethyl) 6 (1 methylpyrazol 4 yl) 3,4 dihydro 2h quinolin 1 yl] n methyl quinoline 6 carboxamide; 5 bromo 3 methyl 1,3 benzothiazol 2 one; 5 [7 (difluoromethyl) 6 (1 methyl 1h pyrazol 4 yl) 3,4 dihydroquinolin 1(2h) yl) 3 methyl 3,4 dihydroquinoxalin 2(1h) one; 5 [7 (difluoromethyl) 6 (1 methyl 1h pyrazol 4 yl) 3,4 dihydroquinolin 1(2h) yl] 1 [[2 (trimethylsilyl)ethoxy]methyl] 1h indole 3 carboxylic acid; 5 [7 (difluoromethyl) 6 (1 methyl 1h pyrazol 4 yl) 3,4 dihydroquinolin 1(2h) yl] 7 isopropyl n methyl 1h pyrrolo[2,3 c]pyridine 3 carboxamide; 5 [7 (difluoromethyl) 6 (1 methyl 1h pyrazol 4 yl) 3,4 dihydroquinolin 1(2h) yl] n methyl 1h ndole 3 carboxamide; 5 [7 (difluoromethyl) 6 (1 methyl 1h pyrazol 4 yl) 3,4 dihydroquinolin 1(2h) yl] n methyl-1h indole 3 carboxamide; 5 [7 (difluoromethyl) 6 (1 methylpyrazol 4 yl) 3,4 dihydro 2h quinolin 1 yl] 3 methyl 1,3 benzothiazol 2 one; 5 [7 (difluoromethyl) 6 (1 methylpyrazol 4 yl) 3,4 dihydro 2h quinolin 1 yl] n methyl pyrazolo[1,5 a]pyrimidine 3 carboxamide; 6 acetyl 3 [7 (difluoromethyl) 6 (1 methylpyrazol 4 yl) 3,4 dihydro 2h quinolin 1 yl] 1 methyl 7,8 dihydro 5h 1,6 naphthyridin 2 one; 6 [7 (difluoromethyl) 6 (1 methyl 1h pyrazol 4 yl) 3,4 dihydroquinolin 1(2h) yl] 4 methoxypyridin 2 amine; 6 [7 (difluoromethyl) 6 (1 methylpyrazol 4 yl) 3,4 dihydro 2h quinolin 1 yl] 4 methyl 1,3,4,5 tetrahydro 1,5 benzodiazepin 2 one; 7 [7 (difluoromethyl) 6 (1 methylpyrazol 4 yl) 3,4 dihydro 2h quinolin 1 yl] 1 methyl 3,4 dihydroquinolin 2 one; bromodomain inhibitor; cyclic adenosine monophosphate response element binding Protein binding protein; cyclic adenosine monophosphate response element binding protein binding protein inhibitor; cyclic AMP binding protein; ethyl 5 [7 (difluoromethyl) 6 (1 methylpyrazol 4 yl) 3,4 dihydro 2h quinolin 1 yl]pyrazolo[1,5 a]pyrimidine 3 carboxylate; methyl 4 [7 (difluoromethyl) 6 (1 methylpyrazol 4 yl) 3,4 dihydro 2h quinolin 1 yl]quinoline 6 carboxylate; quinoline derivative; tert butyl 3 bromo 1 methyl 2 oxo 7,8 dihydro 5h 1,6 naphthyridine 6 carboxylate; tert butyl 3 bromo 2 oxo 1,5,7,8 tetrahydro 1,6 naphthyridine 6 carboxylate; tert butyl [6 [7 (difluoromethyl) 6 (1 methyl 1h pyrazol 4 yl) 3,4 dihydroquinolin 1(2h) yl] 4 methoxypyridin 2 yl)carbamate; unclassified drug; unindexed drug; 1,2,3,4-tetrahydroquinoline; asparagine; BRD4 protein, human; GNE-781; histone acetyltransferase PCAF; nuclear protein; pyrazole derivative; pyridine derivative; quinoline derivative; transcription factor; animal cell; Article; drug bioavailability; drug design; drug potency; drug selectivity; EC50; epigenetics; female; hepatic clearance; human; human cell; hybridization; in vitro study; in vivo study; limit of quantitation; liver microsome; metabolic stability; mouse; nonhuman; pharmacokinetic parameters; pharmacophore; rat; structure activity relation; animal; antagonists and inhibitors; binding site; chemistry; fluorescence resonance energy transfer; high throughput screening; inbred mouse strain; metabolism; molecular docking; procedures; protein domain; X ray crystallography; Animals; Asparagine; Binding Sites; Crystallography, X-Ray; Female; Fluorescence Resonance Energy Transfer; High-Throughput Screening Assays; Mice, Inbred Strains; Molecular Docking Simulation; Nuclear Proteins; p300-CBP Transcription Factors; Protein Domains; Pyrazoles; Pyridines; Quinolines; Transcription Factors