Open AccessDesign and Synthesis of LM146, a Potent Inhibitor of PB1 with an Improved Selectivity Profile over SMARCA2
Author(s) -
Léa Mélin,
Emily M. Gesner,
Sarah Attwell,
Olesya A. Kharenko,
Edward Htun van der Horst,
Henrik C. Hansen,
Alexandre Gag
Publication year - 2021
Publication title -
acs omega
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.779
H-Index - 40
ISSN - 2470-1343
DOI - 10.1021/acsomega.1c01555
Subject(s) - bromodomain , nucleosome , chromatin , chemistry , chromatin remodeling , brd4 , computational biology , selectivity , microbiology and biotechnology , protein subunit , histone , biophysics , biochemistry , biology , dna , gene , catalysis
PB1 is a bromodomain-containing protein hypothesized to act as the nucleosome-recognition subunit of the PBAF complex. Although PB1 is a key component of the PBAF chromatin remodeling complex, its exact role has not been elucidated due to the lack of potent and selective inhibitors. Chemical probes that target specific bromodomains within the complex would constitute highly valuable tools to characterize the function and therapeutic pertinence of PB1 and of each of its bromodomains. Here, we report the design and synthesis of lead compound LM146 , which displays strong stabilization of the second and fifth bromodomains of PB1 as shown by DSF. LM146 does not interact with bromodomains outside of sub-family VIII and binds to PB1(2), PB1(5), and SMARCA2B with K D values of 110, 61, and 2100 nM, respectively, providing a ∼34-fold selectivity profile for PB1(5) over SMARCA2.