Pyridoimidazolones as Novel Potent Inhibitors of v-Raf Murine Sarcoma Viral Oncogene Homologue B1 (BRAF)

Meta-C–H amination and meta-C–H alkynylation of aniline and phenol substrates using a modified norbornene (methyl bicyclo[2.2.1]hept-2-ene-2-carboxylate) as a transient mediator has been developed for the first time. Both the identification of a mono-protected 3-amino-2-hydroxypyridine/pyridone type ligand and the use of a modified norbornene as a mediator are crucial for the realization of these two unprecedented meta-C–H transformations. A variety of substrates are compatible with both meta-C–H amination and meta-C–H alkynylation. Amination and alkynylation of heterocyclic substrates including indole, indoline, and indazole afford the desired products in moderate to high yields.

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“…Notably, the 3-fluoro-5-morpholinoaniline 7 is a key intermediate in the synthesis of 8 , a BRAF inhibitor. 13 …”

Section: Resultsmentioning

confidence: 99%

Ligand-Promoted meta-C–H Amination and Alkynylation

et al. 2016

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“…The novel 4-PAPU pharmacophore illustrated in Figure 4 fits the pharmacophore model of type II inhibitors (15,16): The pyrimidine group is the hinge-binding moiety (HBM) connected through a nitrogen atom to the central phenyl that is expected to occupy the DFG-out pocket (BP-II). The central phenyl and the R 1 substituted terminal phenyl are linked by urea group which functions as the H-donor/acceptor to interact with the side chain of a conserved glutamic acid in the aC helix and with the backbone amide of aspartic acid in the DFG motif.…”

Section: Methodsmentioning

confidence: 97%

“…Dimethyl-6-(4-methylpiperazin-1-yl)-N-(3nitrophenyl)pyrimidin-4-amine(16) A mixture of 14 (4.99 g, 17.9 mmol) and 1-methylpiperazine (10.77 g, 107.5 mmol) in DMSO (20 mL) was stirred under nitrogen at 140°C for 20 min. After cooled to 80°C, the obtained reaction was poured into ice-cold water (200 mL) under stirring and extracted with methylene chloride (2 9 150 mL).…”

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confidence: 99%

Identification of Type II Inhibitors Targeting BRAF Using Privileged Pharmacophores

et al. 2013

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V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) is the most frequently mutated protein kinase in human cancers. The most common mutant BRAF V600E constitutively activates the RAS/RAF/MEK/ERK signaling pathway. BRAF has been validated as an important therapeutic target in human cancers. Phenylaminopyrimidine and unsymmetrical diaryl urea are two privileged pharmacophores in kinase inhibitor drug discovery. Herein, we describe the design of a novel hybrid pharmacophore, 4-phenylaminopyrimidine urea, using the above two pharmacophores. A new series of compounds were in turn synthesized and evaluated to successfully identify selective inhibitors of BRAF and oncogenic BRAF V600E. Once daily oral dosing of lead compound 3 demonstrated sustained antitumor efficacy in A549 human non-small-cell lung cancer xenograft model. Molecular docking suggested that compound 3 might be a type II kinase inhibitor binding to the DFG-out conformation of BRAF.

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“…When the methyl carboxamide chain linked to the pyridine ring of Sorafenib is changed with a fused imidazolone moiety, a series of good BRAF inhibitors is obtained [66]. In this structure four key elements may be identified: the pyridoimidazolone, able to interact with the hinge region, the central phenyl ring that occupies the DFG-out pocket, a hydrogen bond donor/acceptor and the terminal phenyl ring that fills the lipophilic pocket formed in the DFG-out.…”

Section: Pyridoimidazolone Derivativesmentioning

confidence: 99%

Non-ATP Competitive Protein Kinase Inhibitors

Garuti¹,

Roberti²,

Bottegoni

2010

CMC

111

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Protein kinases represent an attractive target in oncology drug discovery. Most of kinase inhibitors are ATP-competitive and are called type I inhibitors. The ATP-binding pocket is highly conserved among members of the kinase family and it is difficult to find selective agents. Moreover, the ATP-competitive inhibitors must compete with high intracellular ATP levels leading to a discrepancy between IC50s measured by biochemical versus cellular assays. The non-ATP competitive inhibitors, called type II and type III inhibitors, offer the possibility to overcome these problems. These inhibitors act by inducing a conformational shift in the target enzyme such that the kinase is no longer able to function. In the DFG-out form, the phenylalanine side chain moves to a new position. This movement creates a hydrophobic pocket available for occupation by the inhibitor. Some common features are present in these inhibitors. They contain a heterocyclic system that forms one or two hydrogen bonds with the kinase hinge residue. They also contain a hydrophobic moiety that occupies the pocket formed by the shift of phenylalanine from the DFG motif. Moreover, all the inhibitors bear a hydrogen bond donor-acceptor pair, usually urea or amide, that links the hinge-binding portion to the hydrophobic moiety and interacts with the allosteric site. Examples of non ATP-competitive inhibitors are available for various kinases. In this review small molecules capable of inducing the DFG-out conformation are reported, especially focusing on structural feature, SAR and biological properties.

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Pyridoimidazolones as Novel Potent Inhibitors of v-Raf Murine Sarcoma Viral Oncogene Homologue B1 (BRAF)

Cited by 38 publications

References 19 publications

Ligand-Promoted meta-C–H Amination and Alkynylation

Ligand-Promoted meta-C–H Amination and Alkynylation

Identification of Type II Inhibitors Targeting BRAF Using Privileged Pharmacophores

Non-ATP Competitive Protein Kinase Inhibitors

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