4-Methyl-1,2,3-Triazoles asN-Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity

Huarui Cui, Angela S. Carlson, Mary A. Schleiff, Anand Divakaran, Jorden A. Johnson, Caroline R. Buchholz, Huda Zahid, Nora R. Vail, Ke Shi, Hideki Aihara, Daniel A. Harki, Grover P. Miller, Joseph J. Topczewski, William C.K. Pomerantz

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


The bromodomain and extra terminal (BET) protein family recognizes acetylated lysines within histones and transcription factors using two N-terminal bromodomains, D1 and D2. The protein-protein interactions between BET bromodomains, acetylated histones, and transcription factors are therapeutic targets for BET-related diseases, including inflammatory disease and cancer. Prior work demonstrated that methylated-1,2,3-triazoles are suitableN-acetyl lysine mimetics for BET inhibition. Here we describe a structure-activity relationship study of triazole-based inhibitors that improve affinity, D1 selectivity, and microsomal stability. These outcomes were accomplished by targeting a nonconserved residue, Asp144 and a conserved residue, Met149, on BRD4 D1. The lead inhibitors DW34 and 26 have a BRD4 D1Kdof 12 and 6.4 nM, respectively. Cellular activity was demonstrated through suppression of c-Myc expression in MM.1S cells and downregulation of IL-8 in TNF-α-stimulated A549 cells. These data indicate that DW34 and 26 are new leads to investigate the anticancer and anti-inflammatory activity of BET proteins.

Original languageEnglish (US)
Pages (from-to)10497-10511
Number of pages15
JournalJournal of medicinal chemistry
Issue number14
StatePublished - Jul 22 2021

Bibliographical note

Funding Information:
This research was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494. A.C. was supported by the Wayland E. Noland Fellowship and UMN Doctoral Dissertation Fellowship. This research was also supported by the National Institute of General Medical Sciences of the National Institutes of Health under award numbers R35GM124718 (J.J.T.) and R35GM140837 (W.C.K.P) . We also acknowledge NIH Shared Instrumentation grant number S10OD011952. Further support for this research was from the NIH (R35-GM118047 to H.A.), and A.D. and C.R.B. were supported by the NIH chemistry–biology interface training grant (T32-GM132029–02) A.D. was also supported by a University of Minnesota Doctoral Dissertation Fellowship. H.Z. was supported by a IEM doctoral fellowship. M.S. was supported by the NIGMS Systems Pharmacology and Toxicology Training grant (T32-GM106999). M.S. and G.M. were supported by Winthrop P. Rockefeller Cancer Institute Team Science Award. D.H. acknowledges funding from the Masonic Cancer Center at the University of Minnesota with resources from Minnesota Masonic Charities. This work is based on research conducted at the NE-CAT beamlines at the Advanced Photon Source, which is supported by the NIH (P30-GM124165). The Pilatus 6 M detector on 24-ID-C beamline is funded by a NIH-ORIP HEI grant (S10-RR029205). We thank staff at the NE-CAT beamlines for assistance in data collection.

Publisher Copyright:
© 2021 American Chemical Society

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


Dive into the research topics of '4-Methyl-1,2,3-Triazoles asN-Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity'. Together they form a unique fingerprint.

Cite this