TY - JOUR
T1 - A Structure-based Design Approach for Generating High Affinity BRD4 D1-Selective Chemical Probes
AU - Cui, Huarui
AU - Divakaran, Anand
AU - Hoell, Zachariah J.
AU - Ellingson, Mikael O.
AU - Scholtz, Cole R.
AU - Zahid, Huda
AU - Johnson, Jorden A.
AU - Griffith, Elizabeth C.
AU - Gee, Clifford T.
AU - Lee, Amani L.
AU - Khanal, Shalil
AU - Shi, Ke
AU - Aihara, Hideki
AU - Shah, Vijay H.
AU - Lee, Richard E.
AU - Harki, Daniel A.
AU - Pomerantz, William C.K.
N1 - Publisher Copyright:
©
PY - 2022/2/10
Y1 - 2022/2/10
N2 - Chemical probes for epigenetic proteins are essential tools for dissecting the molecular mechanisms for gene regulation and therapeutic development. The bromodomain and extra-terminal (BET) proteins are master transcriptional regulators. Despite promising therapeutic targets, selective small molecule inhibitors for a single bromodomain remain an unmet goal due to their high sequence similarity. Here, we address this challenge via a structure-activity relationship study using 1,4,5-trisubstituted imidazoles against the BRD4 N-terminal bromodomain (D1). Leading compounds 26 and 30 have 15 and 18 nM affinity against BRD4 D1 and over 500-fold selectivity against BRD2 D1 and BRD4 D2 via ITC. Broader BET selectivity was confirmed by fluorescence anisotropy, thermal shift, and CETSA. Despite BRD4 engagement, BRD4 D1 inhibition was unable to reduce c-Myc expression at low concentration in multiple myeloma cells. Conversely, for inflammation, IL-8 and chemokine downregulation were observed. These results provide new design rules for selective inhibitors of an individual BET bromodomain.
AB - Chemical probes for epigenetic proteins are essential tools for dissecting the molecular mechanisms for gene regulation and therapeutic development. The bromodomain and extra-terminal (BET) proteins are master transcriptional regulators. Despite promising therapeutic targets, selective small molecule inhibitors for a single bromodomain remain an unmet goal due to their high sequence similarity. Here, we address this challenge via a structure-activity relationship study using 1,4,5-trisubstituted imidazoles against the BRD4 N-terminal bromodomain (D1). Leading compounds 26 and 30 have 15 and 18 nM affinity against BRD4 D1 and over 500-fold selectivity against BRD2 D1 and BRD4 D2 via ITC. Broader BET selectivity was confirmed by fluorescence anisotropy, thermal shift, and CETSA. Despite BRD4 engagement, BRD4 D1 inhibition was unable to reduce c-Myc expression at low concentration in multiple myeloma cells. Conversely, for inflammation, IL-8 and chemokine downregulation were observed. These results provide new design rules for selective inhibitors of an individual BET bromodomain.
UR - http://www.scopus.com/inward/record.url?scp=85123312924&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123312924&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c01779
DO - 10.1021/acs.jmedchem.1c01779
M3 - Article
C2 - 35007061
AN - SCOPUS:85123312924
SN - 0022-2623
VL - 65
SP - 2342
EP - 2360
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -