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

[41] Discovery of potent, selective and orally bioavailable phenylailanine based dipeptidyl peptioase IV inhibitors
Xu, JY
Wei, L
Mathvink, R
He, JF
Park, YJ
He, HB
Leiting, B
Lyons, KA
Marsilio, F
Patel, RA
Wu, JK
Thornberry, NA
Weber, AE
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2005, 229 : U145 - U145
[42] Discovery and optimization of orally bioavailable, selective and potent ATP-independent Akt inhibitors
Chan, Thomas C. K.
Ashwell, Mark A.
Lapierre, Jean-Marc
Brassard, Christopher
Bull, Cathy
Cornell-Kennon, Susan
Eathiraj, Sudharshan
France, Dennis S.
Hill, Jason
Koerner, Steffi
Kelleher, Eoin
Kizer, Darin
Liu, Yanbin
Link, Jeff
Makhija, Sapna
Moussa, Magdi
Namdev, Nivedita
Nicewonger, Robert
Uppalapati, Uma
Palma, Rocio
Szwaya, Jeff
Tandon, Manish
Vensel, David
Volak, Laurie
Volckova, Erika
Westland, Neil
Wu, Hui
Yang, Rui-Yang
CANCER RESEARCH, 2012, 72
[43] Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors
Chan, Shingpan
Zhang, Yunong
Wang, Jie
Yu, Qiuchun
Peng, Xia
Zou, Jian
Zhou, Licheng
Tan, Li
Duan, Yunxin
Zhou, Yang
Hur, Hoon
Ai, Jing
Wang, Zhen
Ren, Xiaomei
Zhang, Zhang
Ding, Ke
JOURNAL OF MEDICINAL CHEMISTRY, 2022, 65 (22) : 15374 - 15390
[44] Structure-Guided Strategy for the Development of Potent Bivalent ERK Inhibitors
Lechtenberg, Bernhard C.
Mace, Peter D.
Sessions, E. Hampton
Williamson, Robert
Stalder, Romain
Wallez, Yann
Roth, Gregory P.
Ried, Stefan J.
Pasquale, Elena B.
ACS MEDICINAL CHEMISTRY LETTERS, 2017, 8 (07): : 726 - 731
[45] Structure-guided design of a potent Clostridiodes difficile toxin A inhibitor
Hussack, Greg
Rossotti, Martin A.
van Faassen, Henk
Murase, Tomohiko
Eugenio, Luiz
Schrag, Joseph D.
Ng, Kenneth K. -S.
Tanha, Jamshid
FRONTIERS IN MICROBIOLOGY, 2023, 14
[46] Discovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist
Hoashi, Yasutaka
Takai, Takafumi
Kosugi, Yohei
Nakashima, Masato
Nakayama, Masaharu
Hirai, Keisuke
Uchikawa, Osamu
Koike, Tatsuki
JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (06) : 3059 - 3074
[47] Structure-guided discovery of potent, dual acting human parainfluenza virus haemagglutinin-neuraminidase inhibitors
Dirr, Larissa
Guillon, Patrice
El-Deeb, Ibrahim
Winger, Moritz
Bailly, Benjamin
Haselhorst, Thomas
Dyason, Jeffrey C.
von Itzstein, Mark
GLYCOBIOLOGY, 2014, 24 (11) : 1127 - 1127
[48] Structure-guided discovery of potent and dual-acting human parainfluenza virus haemagglutinin–neuraminidase inhibitors
Patrice Guillon
Larissa Dirr
Ibrahim M. El-Deeb
Moritz Winger
Benjamin Bailly
Thomas Haselhorst
Jeffrey C. Dyason
Mark von Itzstein
Nature Communications, 5
[49] Structure-guided discovery of cyclin-dependent kinase inhibitors
Fischmann, Thierry O.
Hruza, Alan
Duca, Jose S.
Ramanathan, Lata
Mayhood, Todd
Windsor, William T.
Le, Hung V.
Guzi, Thimothy J.
Dwyer, Michael P.
Paruch, Kamil
Doll, Ronald J.
Lees, Emma
Parry, David
Seghezzi, Wolfgang
Madison, Vincent
BIOPOLYMERS, 2008, 89 (05) : 372 - 379
[50] Fragment-based and structure-guided discovery of perforin inhibitors
Jose, Jiney
Law, Ruby H. P.
Leung, Eleanor W. W.
Wai, Dorothy C. C.
Akhlaghi, Hedieh
Chandrashekaran, Indu R.
Caradoc-Davies, Tom T.
Voskoboinik, Ilia
Feutrill, John
Middlemiss, David
Jeevarajah, Devadharshini
Bashtannyk-Puhalovich, Tanya
Giddens, Anna C.
Lee, Tet Woo
Jamieson, Stephen M. F.
Trapani, Joseph A.
Whisstock, James C.
Spicer, Julie A.
Norton, Raymond S.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2023, 261

← 1 2 3 4 5 →