TY - JOUR
T1 - Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors
AU - Carlson, Angela S.
AU - Cui, Huarui
AU - Divakaran, Anand
AU - Johnson, Jorden A.
AU - Brunner, Ryan M.
AU - Pomerantz, William C.K.
AU - Topczewski, Joseph J.
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/9/12
Y1 - 2019/9/12
N2 - The Bromodomain and Extra Terminal (BET) family of proteins recognize post-translational N-ϵ-acetylated lysine modifications, regulating transcription as "reader" proteins. Bromodomain inhibitors are interesting targets for the development of potential cancer, inflammation, and heart disease treatments. Several dual kinase-bromodomain inhibitors have been identified by screening kinase inhibitor libraries against BET proteins. Although potentially useful from a polypharmacology standpoint, multitarget binding complicates deciphering molecular mechanisms. This report describes a systematic approach to mitigating kinase activity in a dual kinase-bromodomain inhibitor based on a 1,2,3-triazole-pyrimidine core. By modifying the triazole substituent and altering the pyrimidine core, this structure-activity relationship study enhanced BET activity while reducing the p38α kinase activity >90,000-fold. A BRD4-D1 cocrystal structure indicates that the 1,2,3-triazole is acting as a N-ϵ-acetylated lysine mimic. A BRD4 sensitive cell line, MM.1S, was used to demonstrate activity in cells, which is further supported by reduced c-Myc expression.
AB - The Bromodomain and Extra Terminal (BET) family of proteins recognize post-translational N-ϵ-acetylated lysine modifications, regulating transcription as "reader" proteins. Bromodomain inhibitors are interesting targets for the development of potential cancer, inflammation, and heart disease treatments. Several dual kinase-bromodomain inhibitors have been identified by screening kinase inhibitor libraries against BET proteins. Although potentially useful from a polypharmacology standpoint, multitarget binding complicates deciphering molecular mechanisms. This report describes a systematic approach to mitigating kinase activity in a dual kinase-bromodomain inhibitor based on a 1,2,3-triazole-pyrimidine core. By modifying the triazole substituent and altering the pyrimidine core, this structure-activity relationship study enhanced BET activity while reducing the p38α kinase activity >90,000-fold. A BRD4-D1 cocrystal structure indicates that the 1,2,3-triazole is acting as a N-ϵ-acetylated lysine mimic. A BRD4 sensitive cell line, MM.1S, was used to demonstrate activity in cells, which is further supported by reduced c-Myc expression.
KW - BET
KW - BRD4
KW - Bromodomains
KW - kinases
KW - p38α
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U2 - 10.1021/acsmedchemlett.9b00227
DO - 10.1021/acsmedchemlett.9b00227
M3 - Article
C2 - 31531200
AN - SCOPUS:85070800751
SN - 1948-5875
VL - 10
SP - 1296
EP - 1301
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 9
ER -