Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors

Angela S. Carlson, Huarui Cui, Anand Divakaran, Jorden A. Johnson, Ryan M. Brunner, William C Pomerantz, Joseph J Topczewski

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1296-1301
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume10
Issue number9
DOIs
StatePublished - Sep 12 2019

Fingerprint

Triazoles
Phosphotransferases
Lysine
Polypharmacology
Proteins
Transcription
Structure-Activity Relationship
Libraries
Heart Diseases
Screening
Cells
Inflammation
Cell Line
Neoplasms

Keywords

  • BET
  • BRD4
  • Bromodomains
  • kinases
  • p38α

PubMed: MeSH publication types

  • Journal Article

Cite this

Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors. / Carlson, Angela S.; Cui, Huarui; Divakaran, Anand; Johnson, Jorden A.; Brunner, Ryan M.; Pomerantz, William C; Topczewski, Joseph J.

In: ACS Medicinal Chemistry Letters, Vol. 10, No. 9, 12.09.2019, p. 1296-1301.

Research output: Contribution to journalArticle

Carlson, Angela S. ; Cui, Huarui ; Divakaran, Anand ; Johnson, Jorden A. ; Brunner, Ryan M. ; Pomerantz, William C ; Topczewski, Joseph J. / Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors. In: ACS Medicinal Chemistry Letters. 2019 ; Vol. 10, No. 9. pp. 1296-1301.
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