Abstract
As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-ϵ-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-κB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38α. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 9316-9334 |
| Number of pages | 19 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 61 |
| Issue number | 20 |
| DOIs | |
| State | Published - Oct 25 2018 |
Fingerprint
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
Cite this
Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor. / Divakaran, Anand; Talluri, Siva K.; Ayoub, Alex M.; Mishra, Neeraj K; Cui, Huarui; Widen, John C.; Berndt, Norbert; Zhu, Jin Yi; Carlson, Angela S; Topczewski, Joseph J; Schonbrunn, Ernst K.; Harki, Daniel A; Pomerantz, William C.
In: Journal of Medicinal Chemistry, Vol. 61, No. 20, 25.10.2018, p. 9316-9334.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor
AU - Divakaran, Anand
AU - Talluri, Siva K.
AU - Ayoub, Alex M.
AU - Mishra, Neeraj K
AU - Cui, Huarui
AU - Widen, John C.
AU - Berndt, Norbert
AU - Zhu, Jin Yi
AU - Carlson, Angela S
AU - Topczewski, Joseph J
AU - Schonbrunn, Ernst K.
AU - Harki, Daniel A
AU - Pomerantz, William C
PY - 2018/10/25
Y1 - 2018/10/25
N2 - As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-ϵ-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-κB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38α. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.
AB - As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-ϵ-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-κB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38α. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.
UR - http://www.scopus.com/inward/record.url?scp=85055120156&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055120156&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b01248
DO - 10.1021/acs.jmedchem.8b01248
M3 - Article
C2 - 30253095
AN - SCOPUS:85055120156
VL - 61
SP - 9316
EP - 9334
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 20
ER -