Literature DB >> 30268702

Discovery and lead identification of quinazoline-based BRD4 inhibitors.

Shyh-Ming Yang1, Daniel J Urban2, Makoto Yoshioka3, Jeffrey W Strovel3, Steven Fletcher4, Amy Q Wang2, Xin Xu2, Pranav Shah2, Xin Hu2, Matthew D Hall2, Ajit Jadhav2, David J Maloney5.   

Abstract

A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of 48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization.
Copyright © 2018 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  BET inhibitor; BRD4; Bromodomain; Cancer; Inflammation; Quinazoline

Mesh：

Substances：

Year:  2018        PMID： 30268702      PMCID： PMC7392372          DOI： 10.1016/j.bmcl.2018.08.039

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  14 in total

1.  Disrupting Acetyl-Lysine Recognition: Progress in the Development of Bromodomain Inhibitors.

Authors:  F Anthony Romero; Alexander M Taylor; Terry D Crawford; Vickie Tsui; Alexandre Côté; Steven Magnuson
Journal:  J Med Chem       Date:  2015-12-01       Impact factor: 7.446

Review 2.  Beating the odds: BETs in disease.

Authors:  Chen-Yi Wang; Panagis Filippakopoulos
Journal:  Trends Biochem Sci       Date:  2015-07-03       Impact factor: 13.807

Review 3.  Phenotypic screening and fragment-based approaches to the discovery of small-molecule bromodomain ligands.

Authors:  Laura E Jennings; Angelina R Measures; Brian G Wilson; Stuart J Conway
Journal:  Future Med Chem       Date:  2014-02       Impact factor: 3.808

4.  Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor.

Authors:  Keith F McDaniel; Le Wang; Todd Soltwedel; Steven D Fidanze; Lisa A Hasvold; Dachun Liu; Robert A Mantei; John K Pratt; George S Sheppard; Mai H Bui; Emily J Faivre; Xiaoli Huang; Leiming Li; Xiaoyu Lin; Rongqi Wang; Scott E Warder; Denise Wilcox; Daniel H Albert; Terrance J Magoc; Ganesh Rajaraman; Chang H Park; Charles W Hutchins; Jianwei J Shen; Rohinton P Edalji; Chaohong C Sun; Ruth Martin; Wenqing Gao; Shekman Wong; Guowei Fang; Steven W Elmore; Yu Shen; Warren M Kati
Journal:  J Med Chem       Date:  2017-10-12       Impact factor: 7.446

5.  Efficient conversion of Biginelli 3,4-dihydropyrimidin-2(1H)-one to pyrimidines via PyBroP-mediated coupling.

Authors:  Fu-An Kang; Jason Kodah; Qunying Guan; Xiaobing Li; William V Murray
Journal:  J Org Chem       Date:  2005-03-04       Impact factor: 4.354

Review 6.  Bromodomains: Structure, function and pharmacology of inhibition.

Authors:  Elena Ferri; Carlo Petosa; Charles E McKenna
Journal:  Biochem Pharmacol       Date:  2015-12-18       Impact factor: 5.858

Review 7.  Progress in the development and application of small molecule inhibitors of bromodomain-acetyl-lysine interactions.

Authors:  David S Hewings; Timothy P C Rooney; Laura E Jennings; Duncan A Hay; Christopher J Schofield; Paul E Brennan; Stefan Knapp; Stuart J Conway
Journal:  J Med Chem       Date:  2012-09-27       Impact factor: 7.446

Review 8.  Bromodomains as therapeutic targets.

Authors:  Susanne Muller; Panagis Filippakopoulos; Stefan Knapp
Journal:  Expert Rev Mol Med       Date:  2011-09-13       Impact factor: 5.600

Review 9.  Drug Discovery Targeting Bromodomain-Containing Protein 4.

Authors:  Zhiqing Liu; Pingyuan Wang; Haiying Chen; Eric A Wold; Bing Tian; Allan R Brasier; Jia Zhou
Journal:  J Med Chem       Date:  2017-03-02       Impact factor: 7.446

10.  Selective inhibition of BET bromodomains.

Authors:  Panagis Filippakopoulos; Jun Qi; Sarah Picaud; Yao Shen; William B Smith; Oleg Fedorov; Elizabeth M Morse; Tracey Keates; Tyler T Hickman; Ildiko Felletar; Martin Philpott; Shonagh Munro; Michael R McKeown; Yuchuan Wang; Amanda L Christie; Nathan West; Michael J Cameron; Brian Schwartz; Tom D Heightman; Nicholas La Thangue; Christopher A French; Olaf Wiest; Andrew L Kung; Stefan Knapp; James E Bradner
Journal:  Nature       Date:  2010-09-24       Impact factor: 49.962
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  3 in total

1.  Lead optimization and efficacy evaluation of quinazoline-based BET family inhibitors for potential treatment of cancer and inflammatory diseases.

Authors:  Shyh-Ming Yang; Makoto Yoshioka; Jeffrey W Strovel; Daniel J Urban; Xin Hu; Matthew D Hall; Ajit Jadhav; David J Maloney
Journal:  Bioorg Med Chem Lett       Date:  2019-03-12       Impact factor: 2.823

2.  CN470 is a BET/CBP/p300 multi-bromodomain inhibitor and has an anti-tumor activity against MLL-rearranged acute lymphoblastic leukemia.

Authors:  Natsuki Imayoshi; Makoto Yoshioka; Kuniaki Tanaka; Shyh-Ming Yang; Koshi Akahane; Yuki Toda; Shigekuni Hosogi; Takeshi Inukai; Seiji Okada; David J Maloney; Tatsutoshi Nakahata; Junko Takita; Itaru Kato; Eishi Ashihara
Journal:  Biochem Biophys Res Commun       Date:  2021-12-24       Impact factor: 3.575

3.  A quinazoline-based bromodomain inhibitor, CN210, ameliorates indomethacin-induced ileitis in mice by inhibiting inflammatory cytokine expression.

Authors:  Takehisa Noguchi; Kyosuke Hidaka; Satsuki Kobayashi; Kenjiro Matsumoto; Makoto Yoshioka; Xin Hu; David J Maloney; Shyh-Ming Yang; Shinichi Kato
Journal:  Drug Dev Res       Date:  2021-06-01       Impact factor: 5.004
  3 in total

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