A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm.

We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFRC329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2V617F-positive clone in this PV patient harbors EGFRC329R, thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN samples, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2V617F disease clone in MPN.

Synthesis and spectroscopic and electrochemical characterisation of a conducting polythiophene bearing a chiral beta-substituent: polymerisation of (+)-4,4 bi.

A regioregular head-to-head/ tail-to-tail poly(beta,beta'-disubstituted bithiophene) P1 was synthesised by chemical and electrochemical polymerisation of 2,2'-bithiophene that bears (S)-2-methylbutylsulfanyl chains in the beta and beta'-positions. The polymer was characterised by GPC, NMR and UV/Vis spectroscopy, CD, AFM and by electrochemical and conductivity measurements. The CD spectra of P1 in solutions in which poor solvents are present show interesting features and allow the presence of different optically active species to be distinguished. Upon varying the casting conditions of P1, different relative amounts of grainy and homogeneous aggregated phases were observed in AFM micrographies of films and corresponding negative or positive first Cotton effects were found in the CD spectra. AFM, CD and UV/Vis characterisations were also performed on an electrogenerated optically active polymer PE1, in order to make a comparison with the chemically synthesised one. The interesting, small band gap of P1 allows for easy p- and n-electrochemical doping.

Quantitative structure-activity relationships in dihydropteroate synthase inhibition by multisubstituted sulfones. Design and synthesis of some new derivatives with improved potency.

On the bases of the linear correlation existing for a training set of homomultisubstituted 4-aminodiphenyl sulfones between the computed (INDO) electronic net charges of the SO2 group and the enzymic inhibition data on dihydropteroate synthase from Escherichia coli, seven new heteromultisubstituted derivatives were designed, synthesized, and tested for their inhibition potencies. These compounds were found to be from 5-11 times more effective than 4,4'-diaminodiphenyl sulfone. The implications of the results in the drug design and in the model for the enzyme-inhibitors interaction are discussed.

Quantitative structure-activity analysis in dihydropteroate synthase inhibition by sulfones. Comparison with sulfanilamides.

A set of 25 4'-, eight 2',4'-, and five 2',4',6'-substituted 4-aminodiphenyl sulfones were tested for their inhibitory activity on dihydropteroate synthase of Escherichia coli. Linear regression analysis shows that enzymic inhibition indices correlate well with both quantum chemical and spectroscopic descriptors of the electronic structure of the common moiety 4-NH2-C6H4-SO2 of the sulfones (the above descriptors being expressed in relation to the electronic structure of the enzyme substrate, p-aminobenzoate). Therefore, the biological activity of the sulfones can be related to the electronic structural resemblance between these inhibitors and the substrate of the target enzyme. Since a similar result was previously obtained for a wide series of sulfanilamides in their different (amidic, imidic, and anionic) forms, it appears possible to consider the antibacterial sulfones and sulfanilamides as a congeneric chemical series. On the basis of the present results, the classical theory of antimetabolites would appear to take on a quantitative and sound rationale.