From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors

被引：2

作者：

Koravovic, Mladen ^{[1
]}

Mayasundari, Anand ^{[2
]}

Tasic, Gordana ^{[1
]}

Keramatnia, Fatemeh ^{[2
]}

Stachowski, Timothy R. ^{[2
]}

Cui, Huarui ^{[3
]}

Chai, Sergio C. ^{[2
]}

Jonchere, Barbara ^{[4
]}

Yang, Lei ^{[2
]}

Li, Yong ^{[2
]}

Fu, Xiang ^{[2
]}

Hiltenbrand, Ryan ^{[5
]}

Paul, Leena ^{[6
]}

Mishra, Vibhor ^{[5
]}

Klco, Jeffery M. ^{[5
]}

Roussel, Martine F. ^{[4
]}

Pomerantz, William CK. ^{[3
]}

Fischer, Marcus ^{[2
]}

Rankovic, Zoran ^{[2
]}

Savic, Vladimir ^{[1
]}

机构：

[1] Univ Belgrade, Fac Pharm, Dept Organ Chem, Vojvode Stepe 450, Belgrade 11221, Serbia

[2] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[3] Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA

[4] St Jude Childrens Res Hosp, Dept Tumour Cell Biol, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[5] St Jude Childrens Res Hosp, Dept Pathol, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[6] St Jude Childrens Res Hosp, Dept Dev Neurobiol, 262 Danny Thomas Pl, Memphis, TN 38105 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 251卷

关键词：

BET inhibitors; JQ1; Amides; ACETYL-LYSINE RECOGNITION; DRUG DISCOVERY; BROMODOMAIN PROTEINS; HISTONE ACETYLATION; PERMEABILITY; BIOISOSTERES; SOLUBILITY; MECHANISM; TARGETS; MOTIF;

D O I：

10.1016/j.ejmech.2023.115246

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.

引用

下载

页数：8

共 50 条

[31] Discovery of Novel Pyrazolopyrimidines as Potent, Selective, and Orally Bioavailable Inhibitors of ALK2
Nguyen, Minh H.
Atasoylu, Onur
Wu, Liangxing
Kapilashrami, Kanishk
Pusey, Michelle
Gallagher, Karen
Lai, Cheng-Tsung
Zhao, Peng
Barbosa, Joseph
Liu, Kai
He, Chunhong
Zhang, Colin
Styduhar, Evan D.
Witten, Michael R.
Chen, Yaoyu
Lin, Luping
Yang, Yan-ou
Covington, Maryanne
Diamond, Sharon
Yeleswaram, Swamy
Yao, Wenqing
ACS MEDICINAL CHEMISTRY LETTERS, 2022, : 1159 - 1164
[32] Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase γ Inhibitors
Leahy, James W.
Buhr, Chris A.
Johnson, Henry W. B.
Kim, Byung Gyu
Baik, TaeGon
Cannoy, Jonah
Forsyth, Timothy P.
Jeong, Joon Won
Lee, Matthew S.
Ma, Sunghoon
Noson, Kevin
Wang, Longcheng
Williams, Matthew
Nuss, John M.
Brooks, Eric
Foster, Paul
Goon, Leanne
Heald, Nathan
Holst, Charles
Jaeger, Christopher
Lam, Scott
Lougheed, Julie
Lam Nguyen
Plonowski, Arthur
Song, Joanne
Stout, Thomas
Wu, Xiang
Yakes, Michael F.
Yu, Peiwen
Zhang, Wentao
Lamb, Peter
Raeber, Olivia
JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (11) : 5467 - 5482
[33] Discovery of potent, selective, orally bioavailable Stearoyl-CoA desaturase 1 inhibitors
Liu, Gang
Lynch, John K.
Freeman, Jennifer
Liu, Bo
Xin, Zhili
Zhao, Hongyu
Serby, Michael D.
Kym, Philip R.
Suhar, Tom S.
Smith, Harriet T.
Cao, Ning
Yang, Ruojing
Janis, Rich S.
Krauser, Joel A.
Cepa, Steven P.
Beno, David W. A.
Sham, Hing L.
Collins, Christine A.
Surowy, Teresa K.
Camp, Heidi S.
JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (13) : 3086 - 3100
[34] Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor
Gillman, Kevin W.
Starrett, John E., Jr.
Parker, Michael F.
Xie, Kai
Bronson, Joanne J.
Marcin, Lawrence R.
McElhone, Kate E.
Bergstrom, Carl P.
Mate, Robert A.
Williams, Richard
Meredith, Jere E., Jr.
Burton, Catherine R.
Barten, Donna M.
Toyn, Jeremy H.
Roberts, Susan B.
Lentz, Kimberley A.
Houston, John G.
Zaczek, Robert
Albright, Charles F.
Decicco, Carl P.
Macor, John E.
Olson, Richard E.
ACS MEDICINAL CHEMISTRY LETTERS, 2010, 1 (03): : 120 - 124
[35] Discovery of orally bioavailable Aurora kinase inhibitors
Zhang, Yonglian
Yu, Tao
Tagat, Jayaram R.
Xiao, Yushi
Kerekes, Angela D.
Doll, Ronald J.
Esposite, Sara
Hruza, Alan
Voss, Matthew
Rainka, Matthew
Basso, Andrea D.
Gray, Kimberly
Tevar, Seema
Kirschmeier, Paul
Liu, Ming
Liang, Lianzhu
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2011, 241
[36] Discovery of orally bioavailable Aurora kinase inhibitors
Belanger, David B.
Williams, Michael J.
Meng, Zhaoyang
Yu, Tao
Mandal, Amit K.
Curran, Patrick J.
Rainka, Matthew P.
Shih, Neng-Yang
Siddiqui, M. Arshad
Basso, Andrea D.
Prelusky, Daniel
Liu, Ming
Lee, Suining
Yaremko, Bohdan
Gray, Kimberly
Tevar, Seema
Jones, Jennifer
Smith, Elizabeth B.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2010, 240
[37] Discovery and characterization of the potent, selective and orally bioavailable MMP inhibitor ABT-770
Curtin, ML
Florjancic, AS
Heyman, HR
Michaelides, MR
Garland, RB
Holms, JH
Steinman, DH
Dellaria, JF
Gong, J
Wada, CK
Guo, Y
Elmore, IB
Tapang, P
Albert, DH
Magoc, TJ
Marcotte, PA
Bouska, JJ
Goodfellow, CL
Bauch, JL
Marsch, KC
Morgan, DW
Davidsen, SK
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (12) : 1557 - 1560
[38] Discovery of BMS-562247, a potent and orally bioavailable coagulation factor Xa inhibitor
Pinto, DJP
Orwat, MJ
Fevig, JM
Quan, ML
Galemmo, RA
Koch, S
Li, RH
Clark, C
Cacciola, J
Wells, BL
Drummond, S
Rossi, KA
Alexander, RS
Luettgen, JM
Wong, PC
He, K
Xin, BM
Grossman, SJ
Knabb, RM
Ogletree, ML
Wexler, RR
Lam, PYS
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2005, 230 : U2646 - U2646
[39] Discovery and optimization of orally bioavailable and potent plasma Kallikrein inhibitors bearing a quaternary carbon
Zhang, Weihe
Vadlakonda, Satish
Wu, Minwan
Chintareddy, Venkat
Vogeti, L. N.
Juarez, Luis
Muppa, Saritha
Parker, Cynthia
Kellogg-Yelder, Debra
Williams, Jason
Polach, Kevin
Chen, Xilin
Raman, Krishnan
Babu, Y. S.
Kotian, Pravin
BIOORGANIC & MEDICINAL CHEMISTRY, 2022, 73
[40] Discovery of Biaryl Amides as Potent, Orally Bioavailable, and CNS Penetrant RORγt Inhibitors
Wang, Yonghui
Cai, Wei
Cheng, Yaobang
Yang, Ting
Liu, Qian
Zhang, Guifeng
Meng, Qinghua
Han, Fangbin
Huang, Yafei
Zhou, Ling
Xiang, Zhijun
Zhao, Yong-Gang
Xu, Yan
Cheng, Ziqiang
Lu, Sijie
Wu, Qianqian
Xiang, Jia-Ning
Elliott, John D.
Leung, Stewart
Ren, Feng
Lin, Xichen
ACS MEDICINAL CHEMISTRY LETTERS, 2015, 6 (07): : 787 - 792

← 1 2 3 4 5 →