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

Optimization of maturation of Radio-cephalic Arteriovenous Fistula using a Model Relating Energy Loss Rate and Vascular Geometric Parameters

International audienceThe main reason for the early failure of radio-cephalic arteriovenous fistula (RCAVF) is non-maturity, which means that the blood flow rate in the fistula cannot increase to the expected value for dialysis. From a mechanical perspective, the vascular resistance at the artificially designed anastomosis causes an energy loss that affects blood flow rate growth and leads to early failure. This research studied how to maximize the RCA VF maturity and primary patency by controlling the energy loss rate. We theoretically analyzed and derived a model that evaluates the energy loss rate Eavf in RCAVF as a function of its blood vessel geometric parameters (GPs) for given flow rates. There was an aggregate of five controllable GPs in RCAVF: radial artery diameter (Dra), cephalic vein diameter (Dcv), blood vessel distance between artery and vein (h), anastomotic diameter (Da), and anastomotic angle (). Through this analysis, it was found that Eavf was inversely proportional to Dra, Dcv, Da, and , whereas proportional to h. Therefore, we recommended surgeons choose the vessels with large diameters , close distance, and increase the diameter and angle of the anastomosis to decrease the early failure of RCAVF. Simultaneously, we could explain the results of many clinical empiricisms with our formula. We found that increasing Dcv and were more significant in reducing Eavf than increasing Dra and Da. Based on our model, we could define two critical energy loss rates (CELa, CELb) to help surgeons evaluate the blood vessels and choose the ideal range of . Help them design the preoperative RCAVF plan for each patient to increase the maturity and the primary patency of RCAVF