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

State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
European journal of medicinal chemistry (Impact Factor: 3.27). 02/2012; 50:288-95. DOI: 10.1016/j.ejmech.2012.02.007
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The "RAS/BRAF/MEK/ERK" pathway has been associated with human cancers due to the frequent oncogenic mutations identified in its members. In particular, BRAF is mutated at high frequency in many cancers especially melanoma. This mutation leads to activation of the MAPK signaling pathway, inducing uncontrolled cell proliferation, and facilitating malignant transformation. All these facts make BRAF an ideal target for antitumor therapeutic development. Many BRAF inhibitors have been discovered during the last decade and most of them exhibit potent antitumor activity especially on tumors that harbor BRAF(V600E) mutations. Some of these compounds have entered clinical trials and displayed encouraged results. The present review highlights the progress in identification and development of BRAF inhibitors especially during the last five years.
    European journal of medicinal chemistry 11/2013; 72C:170-205. · 3.27 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The RAF-MEK-ERK cascade appears to be intimately involved in the regulation of cell cycle progression and apoptosis. The BRAF(V600E) mutant results in constitutive activation of the ERK pathway, which can lead to cellular growth dysregulation. A series of 5-phenyl-1H-pyrazol derivatives () have been designed and synthesized, and their biological activities were evaluated as potential BRAF(V600E) inhibitors. All the compounds were reported for the first time except , and compound 1-(4-bromo-2-hydroxybenzyl)-3-phenyl-1-(5-phenyl-1H-pyrazol-3-yl)urea () displayed the most potent inhibitory activity (BRAF(V600E) IC50 = 0.19 μM). Antiproliferative assay results indicated that compound possessed high antiproliferative activity against cell lines WM266.4 and A375 in vitro, with IC50 values of 1.50 and 1.32 μM, respectively, which were comparable with the positive control vemurafenib. Docking simulations showed that compound binds tightly to the BRAF(V600E) active site and acts as BRAF(V600E) inhibitor. A 3D-QSAR model was also built to provide more pharmacophore understanding towards designing new agents with more potent BRAF(V600E) inhibitory activity.
    Organic & Biomolecular Chemistry 08/2013; · 3.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chalcones are naturally occurring compounds exhibiting broad spectrum biological activities including anticancer activity through multiple mechanisms. Literature on anticancer chalcones highlights the employment of three pronged strategies, namely; structural manipulation of both aryl rings, replacement of aryl rings with heteroaryl scaffolds, molecular hybridization through conjugation with other pharmacologically interesting scaffolds for enhancement of anticancer properties. Methoxy substitutions on both the aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings appear to influence anticancer and other activities. Similarly, heterocyclic rings either as ring A or B in chalcones, also influence the anticancer activity shown by this class of compounds. Hybrid chalcones formulated by chemically linking chalcones to other prominent anticancer scaffolds such as pyrrol[2,1-c][1,4]benzodiazepines, benzothiazoles, imidazolones have demonstrated synergistic or additive pharmacological activities. The successful application of these three pronged strategy for discovering novel anticancer agents based on chalcone scaffold has resulted in many novel and chemically diverse chalcones with potential therapeutic application for many types of cancer. This review summarizes the concerted efforts expended on the design and development of anticancer chalcones recorded in recent literature and also provides an overview of the patents published in this area between 2007 to 2013 (WO2013022951, WO201201745, US2012029489).
    Recent Patents on Anti-Cancer Drug Discovery 08/2014; · 2.70 Impact Factor