Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics.
Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348, we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from patients with myeloproliferative neoplasm. Screening across 931 cancer cell lines revealed differential growth inhibitory potential with highest activity against bone and blood cancers and greatly enhanced activity over the single BET inhibitor JQ1. Gene drug sensitivity analyses and drug combination studies indicate synergism of BRD4 and kinase inhibition as a plausible reason for the superior potency in cell killing. Combined, our findings indicate promising potential of these agents as novel chemical probes and cancer therapeutics.Mol Cancer Ther; 16(6); 1054-67. ©2017 AACR.
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida.
Stuart W
SW
Ember
Tumor Biology Department, Moffitt Cancer Center, Tampa, Florida.
Que T
QT
Lambert
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida.
Norbert
N
Berndt
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida.
Steven
S
Gunawan
Chemical Biology Core, Moffitt Cancer Center, Tampa, Florida.
Muhammad
M
Ayaz
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
Marilena
M
Tauro
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida.
Jin-Yi
JY
Zhu
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida.
Paula J
PJ
Cranfill
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
Patricia
P
Greninger
Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida.
Conor C
CC
Lynch
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
Cyril H
CH
Benes
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida.|Chemical Biology Core, Moffitt Cancer Center, Tampa, Florida.
Harshani R
HR
Lawrence
Tumor Biology Department, Moffitt Cancer Center, Tampa, Florida.
Gary W
GW
Reuther
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida. ernst.schonbrunn@moffitt.org nicholas.lawrence@moffitt.org.
Nicholas J
NJ
Lawrence
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida. ernst.schonbrunn@moffitt.org nicholas.lawrence@moffitt.org.
Ernst
E
Schönbrunn
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
D000970:Antineoplastic Agents; D053614:Janus Kinase 2; D047428:Protein Kinase Inhibitors; D011506:Proteins; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins