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

页数：8

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