Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT

International audienceBackground: The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT. Methodology/Principal Findings: In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC50) of 200 ± 40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC50 of 150 ± 80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant. Conclusions: Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicit

The genetics of endophenotypes of neurofunction to understand schizophrenia (GENUS) consortium: a collaborative cognitive and neuroimaging genetics project

Background Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. Methods We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. Results Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p 10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia

Synthetic Approaches to Polyoxygenated Cyclohexanes of Biological Origin.

General approaches to the construction and functionalization of cyclohexane moieties were developed in connection with the total synthesis of shikimate-derived natural products and of metabolites of aromatic hydrocarbons. E,E-1-Trimethylsilyl-4-acetoxy-1,3-butadiene was synthesized from allyltrimethylsilane by a new reaction, in one step. Cycloaddition of the diene to activated dienophiles provided the corresponding adducts in good yield and excellent stereochemical purity. These adducts underwent smooth desilylative transposition to allylic alcohols or halides. Conversion to allylic alcohols was effected by a novel dihydroxylation-dehydroxysilylation reaction of allylsilanes which proceeds in (TURN)90% overall yield. The compounds resulting from such transposition reactions are versatile synthetic precursors to a variety of polyoxygenated cyclohexane natural products, as illustrated in the total synthesis of shikimic acid. The new synthesis of shikimic acid would allow specific ('13)C and /or ('3)H labelling of each ring position. Cycloaddition of E,E-1-trimethylsilyl-4-acetoxyl-1,3-butadiene to arynes proved not to be a viable approach to arene oxides. However, potential precursors to trans-dihydrodiol metabolites of aromatic hydrocarbons were readily obtained by Diels-Alder reaction of 3,4-dioxygenated furans with dehydroaromatics followed by diimide reduction. A search for new, mild epoxide syntheses led to the development of a superoxide-mediated conversion of cyclic cis-1,2-diol dimesylates to the corresponding epoxides with inversion of configuration. The new synthetic method was most effective with fairly rigid systems (steroid nucleus, "locked" cyclohexanes). Products of oxidative cleavage or elimination resulted with 1-aryl-1,2-diol disulfonates.Ph.D.Organic chemistryUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/158608/1/8204622.pd

Synthetic studies on heterocyclic natural products

This paper highlights ongoing efforts toward Erythrina alkaloids, himandrine, tetrodotoxin, and thiopeptide antibiotics such as nosiheptide and describes representative spinoffs in biomedicine that emanated from the author’s research in synthetic organic chemistry. </jats:p