Dual binding site inhibitors of B-RAF kinase

Wolin, Ronald; Bembenek, Scott D.; Wei, Jianmei; Crawford, Shelby; Lundeen, Katherine A.; Brunmark, Anders; Karlsson, Lars; Edwards, James P.; Blevitt, Jonathan M.

doi:10.1016/j.bmcl.2008.04.002

Cited by 14 publications

(9 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As parts of the NADPH cofactor and the MTX or DHF ligand binding sites are proximal to each other, the development of dual-site inhibitors are an attractive prospective. In the past, dual-site inhibitors have been developed against several drug targets (Haviv et al, 2007; Munoz-Ruiz et al, 2005; Wolin et al, 2008). Dual-site inhibitors offer the possibility of improving potency through avidity effects.…”

Section: Introductionmentioning

confidence: 99%

X-ray structure of the ternary MTX·NADPH complex of the anthrax dihydrofolate reductase: A pharmacophore for dual-site inhibitor design

Bennett

Wan

Ahmad

et al. 2009

Journal of Structural Biology

View full text Add to dashboard Cite

For reasons of bioterrorism and drug resistance, it is imperative to identify and develop new molecular points of intervention against anthrax. Dihydrofolate reductase (DHFR) is a highly conserved enzyme and an established target in a number of species for a variety of chemotherapeutic programs. Recently, the crystal structure of B. anthracis DHFR (baDHFR) in complex with methotrexate (MTX) was determined and, based on the structure, proposals were made for drug design strategies directed against the substrate binding site. However, little is gleaned about the binding site for NADPH, the cofactor responsible for hydride transfer in the catalytic mechanism. In the present study, X-ray crystallography at 100 K was used to determine the structure of baDHFR in complex with MTX and NADPH. Although the NADPH binding mode is nearly identical to that seen in other DHFR ternary complex structures, the adenine moiety adopts an off-plane tilt of nearly 90° and this orientation is stabilized by hydrogen bonds to functionally conserved Arg residues. A comparison of the binding site, focusing on this region, between baDHFR and the human enzyme is discussed, with an aim at designing species-selective therapeutics. Indeed, the ternary model, refined to 2.3Å resolution, provides an accurate template for testing the feasibility of identifying dual-site inhibitors, compounds that target both the substrate and cofactor binding site. With the ternary model in hand, using in silico methods, several compounds were identified which could potentially form key bonding contacts in the substrate and cofactor binding sites. Ultimately, two structurally distinct compounds were verified that inhibit baDHFR at low μM concentrations. The apparent Kd for one of these, (2-(3-(2-(hydroxyimino)-2-(pyridine-4-yl)-6,7-dimethylquinoxalin-2-yl)-1-(pyridine-4-yl)ethanone oxime), was measured by fluorescence spectroscopy to be 5.3 μM.

show abstract

Section: Introductionmentioning

confidence: 99%

X-ray structure of the ternary MTX·NADPH complex of the anthrax dihydrofolate reductase: A pharmacophore for dual-site inhibitor design

Bennett

Wan

Ahmad

et al. 2009

Journal of Structural Biology

View full text Add to dashboard Cite

show abstract

“…Among them, the α‐phenylaminoketone Th 2 CONHPh is cyclized with thiocyanate anion to form the imidazol‐2‐thione 15 , which is further converted to the 2‐thiomethylimidazole 16 by the preferential methylation at the sulfur atom (Scheme ) 9. The trifluoromethyl group at the 2‐position of the imidazole ring was introduced by condensation reactions with trifluoroacetaldehyde or its hemiacetal (Scheme ) 10. For the synthesis of the N , N′ ‐diarylimidazolium salt 14 ‐PF 6 , an alternative strategy was used.…”

Section: Resultsmentioning

confidence: 99%

Syntheses and Photochromic Studies of Dithienylethene‐Containing Imidazolium Derivatives and Their Reactivity towards Nucleophiles

Duan

Zhu

Yam

2010

Chemistry A European J

View full text Add to dashboard Cite

A series of dithienylethene-containing imidazolium salts with various substituents on the 2-position of the imidazolium ring has been synthesized. The photochromic properties of these compounds have been studied, and the closed forms are found to be solvatochromic due to the donor-acceptor interaction with the solvent molecules. The closed form of the imidazolium salt shows a much higher affinity towards nucleophiles over the open form of the salt. A reaction pathway has been proposed to account for this reactivity difference based on the structure-property relationship, and the possible structure of the reaction product is discussed.

show abstract

“…BRAF is mutated in a range of cancers with particularly high frequencies in melanoma, ovarian and thyroid cancers. The most common mutation occurs from the replacement of a valine residue with a glutamic acid residue located at position 600 and is termed V 600E [59]. This mutation is responsible for increased kinase activity in many human tumors, validating BRAF as an attractive target for anticancer therapy.…”

Section: Braf Inhibitorsmentioning

confidence: 98%

Non-ATP Competitive Protein Kinase Inhibitors

Garuti¹,

Roberti²,

Bottegoni

2010

CMC

111

View full text Add to dashboard Cite

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.

show abstract

Dual binding site inhibitors of B-RAF kinase

Cited by 14 publications

References 8 publications

X-ray structure of the ternary MTX·NADPH complex of the anthrax dihydrofolate reductase: A pharmacophore for dual-site inhibitor design

X-ray structure of the ternary MTX·NADPH complex of the anthrax dihydrofolate reductase: A pharmacophore for dual-site inhibitor design

Syntheses and Photochromic Studies of Dithienylethene‐Containing Imidazolium Derivatives and Their Reactivity towards Nucleophiles

Non-ATP Competitive Protein Kinase Inhibitors

Contact Info

Product

Resources

About