Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands

Journal of Medicinal Chemistry
David S HewingsStuart J Conway

Abstract

The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.

References

Jan 19, 2000·Nature·B D Strahl, C D Allis
Mar 16, 2000·The EMBO Journal·Tony Kouzarides
Mar 26, 2002·FEBS Letters·Lei Zeng, Ming Ming Zhou
Sep 6, 2011·Cell·Jake E DelmoreConstantine S Mitsiades
Jan 27, 2012·Trends in Pharmacological Sciences·Rab K PrinjhaKevin Lee
Apr 14, 2012·Nature Reviews. Drug Discovery·Cheryl H ArrowsmithMatthieu Schapira
Jun 20, 2012·FEBS Letters·Panagis Filippakopoulos, Stefan Knapp
Jul 12, 2012·ACS Medicinal Chemistry Letters·Dashyant Dhanak
Sep 13, 2012·ACS Medicinal Chemistry Letters·Stuart J Conway

Citations

Oct 23, 2013·Journal of Medicinal Chemistry·Guangtao ZhangMing-Ming Zhou
Apr 23, 2014·Nature Reviews. Drug Discovery·Panagis Filippakopoulos, Stefan Knapp
Jan 29, 2014·Future Medicinal Chemistry·Laura E JenningsStuart J Conway
Nov 23, 2013·Expert Opinion on Therapeutic Patents·Jean-Marc GarnierChristopher J Burns
Jan 6, 2016·Journal of Medicinal Chemistry·Apirat ChaikuadStefan Knapp
Dec 29, 2015·Biochemical Pharmacology·Elena FerriCharles E McKenna
Dec 4, 2015·Organic Letters·Calum W MuirAllan J B Watson
Nov 18, 2015·Journal of Medicinal Chemistry·Frank Anthony RomeroSteven Magnuson
Apr 2, 2014·Biochimica Et Biophysica Acta·Roberto SanchezMing-Ming Zhou
Dec 9, 2014·The Biochemical Journal·Guillaume Poncet-MontangeJohn E Ladbury
May 23, 2015·The Biochemical Journal·Angelika BöttgerAlexander Wolf
Jun 5, 2015·Journal of Medicinal Chemistry·Andrea UnzueCristina Nevado
Apr 10, 2015·Journal of Medicinal Chemistry·Natalie H TheodoulouPhilip G Humphreys
Apr 1, 2014·Drug Discovery Today·Fatima el BahhajPhilippe Bertrand
Oct 23, 2016·Drug Discovery Today. Technologies·Aaron J StonestromGerd A Blobel
Oct 23, 2016·Drug Discovery Today. Technologies·Dimitrios Spiliotopoulos, Amedeo Caflisch
Oct 24, 2015·Chemical Reviews·Guangtao ZhangMing-Ming Zhou
Feb 15, 2017·Journal of Medicinal Chemistry·Zhiqing LiuJia Zhou
Apr 14, 2017·Journal of Medicinal Chemistry·Léa BouchéBernard Haendler
Apr 26, 2016·Organic Chemistry Frontiers : an International Journal of Organic Chemistry·Jess HealyStuart J Conway
Jan 23, 2016·Chemical Science·Matteo AldeghiPhilip C Biggin
Apr 5, 2017·Journal of Medicinal Chemistry·R Aldrin DennyEugene L Piatnitski Chekler
Feb 6, 2014·ChemMedChem·Daniel GallenkampHilmar Weinmann
Jan 13, 2017·Microbiology and Molecular Biology Reviews : MMBR·Victoria JeffersWilliam J Sullivan
Sep 26, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Burcu ÇalışkanErden Banoglu
Oct 16, 2013·ChemMedChem·Stefan Knapp, Hilmar Weinmann
Jun 4, 2016·Oncotarget·Raquel C MontenegroSusanne Müller
Dec 14, 2018·MedChemComm·Yingchao DuanHongmin Liu
Jul 3, 2015·Angewandte Chemie·Ciaran P SeathAllan J B Watson
Jan 11, 2016·ChemMedChem·Natalie H TheodoulouPhilip G Humphreys
Jul 18, 2017·Archiv der Pharmazie·Mostafa Radwan, Rabah Serya

Related Concepts

BRD4 protein, human
CREBBP protein, human
Acetylation
Histone H7
Isoxazoles
Ligands
Enisyl
Nucleolar Proteins
Plasma Protein Binding Capacity
Structure-Activity Relationship

Related Feeds

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease with approximately 20,000 cases per year in the United States. AML also accounts for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. Here is the latest research on this disease.

AML: Role of LSD1 by CRISPR (Keystone)

Find the latest rersearrch on the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML) here.