Design, synthesis and biological evaluation of novel (E)-α-benzylsulfonyl chalcone derivatives as potential BRAF inhibitors

European Journal of Medicinal Chemistry
Qing-Shan LiHai-Liang Zhu

Abstract

Activating mutations in the BRAF serine/threonine kinase are found in more than 70% of human melanomas, >90% of which are BRAF(V600E). It provides new therapeutic opportunities in malignant melanoma. In silico and in vitro screening of our compound collection has identified Hit 2 as BRAF(V600E) inhibitor. Based on its structure, a series of novel (E)-α-benzylsulfonyl chalcone derivatives (13-40) were designed and synthesized. Compound 38 exhibited the most potent inhibitory activity with an IC(50) value of 0.17 μM for BRAF(V600E) and GI(50) value of 0.52 μM for mutant BRAF-dependent cells. The results of cell based pERK activity and cellular selectivity suggested that those compounds could selectively inhibit proliferation of mutant BRAF-dependent melanoma cell line through inhibition of oncogenic BRAF.

References

Apr 1, 1997·Current Opinion in Cell Biology·M J Robinson, M H Cobb
Mar 14, 2000·Current Opinion in Cell Biology·A S Edwards, J D Scott
Mar 10, 2001·Recent Progress in Hormone Research·J AvruchX F Zhang
Jun 18, 2002·Nature·Helen DaviesP Andrew Futreal
Jul 18, 2002·Nature Reviews. Drug Discovery·Margaret A Somerville
Mar 24, 2004·Cell·Paul T C WanUNKNOWN Cancer Genome Project
Apr 3, 2004·Cancer Research·Claudia WellbrockRichard Marais
Jun 23, 2004·Oncogene·Maria KarasaridesRichard Marais
Oct 19, 2004·Cancer Cell·Mathew J Garnett, Richard Marais
Nov 3, 2004·Nature Reviews. Molecular Cell Biology·Claudia WellbrockRichard Marais
Dec 2, 2004·Nature Reviews. Cancer·Judith S Sebolt-Leopold, Roman Herrera
Apr 14, 2005·Molecular Cancer Therapeutics·Srikala S SridharLillian L Siu
Jan 6, 2006·Journal of Medicinal Chemistry·Ion Niculescu-DuvazCaroline J Springer
Sep 5, 2006·Journal of Ethnopharmacology·Mani VasudevanMilind Parle
Feb 3, 2007·Journal of Computational Chemistry·Ruth HueyDavid S Goodsell
Jan 29, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Bret B Friday, Alex A Adjei
Sep 12, 2008·Journal of Medicinal Chemistry·Cheng LuoRonen Marmorstein
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
Mar 2, 2010·Bioorganic & Medicinal Chemistry·M V Ramana ReddyE Premkumar Reddy
Mar 31, 2010·Biochemical Pharmacology·Claudia Wellbrock, Adam Hurlstone
Feb 24, 2011·Journal of Medicinal Chemistry·Alexandra E GouldKatherine M Galvin

❮ Previous
Next ❯

Citations

Jan 16, 2014·European Journal of Medicinal Chemistry·Hala Bakr El-Nassan
Nov 12, 2013·European Journal of Medicinal Chemistry·Ieva KarpavicieneJosé M Padrón
May 26, 2015·European Journal of Medicinal Chemistry·Debarshi Kar MahapatraVivek Asati
May 26, 2015·European Journal of Medicinal Chemistry·Ieva KarpavičienėInga Čikotienė
Feb 3, 2015·Chemistry & Biodiversity·Qing-Shan LiChen-Zhong Liao
Jul 25, 2019·European Journal of Medicinal Chemistry·Shijie ZhaoYumeng Wei
May 29, 2021·RSC Medicinal Chemistry·Kamonpan SanachaiThanyada Rungrotmongkol

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.