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

Cyclin-dependent kinase 2 inhibitors in cancer therapy: an update

Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.Solomon Tadesse, Elizabeth C. Caldon, Wayne Tilley and Shudong Wan

First results of a large-area cryogenic gaseous photomultiplier coupled to a dual-phase liquid xenon TPC

We discuss recent advances in the development of cryogenic gaseous photomultipliers (GPM), for possible use in dark matter and other rare-event searches using noble-liquid targets. We present results from a 10 cm diameter GPM coupled to a dual-phase liquid xenon (LXe) TPC, demonstrating - for the first time - the feasibility of recording both primary ("S1") and secondary ("S2") scintillation signals. The detector comprised a triple Thick Gas Electron Multiplier (THGEM) structure with cesium iodide photocathode on the first element; it was shown to operate stably at 180 K with gains above 10^5, providing high single-photon detection efficiency even in the presence of large alpha particle-induced S2 signals comprising thousands of photoelectrons. S1 scintillation signals were recorded with a time resolution of 1.2 ns (RMS). The energy resolution ({\sigma}/E) for S2 electroluminescence of 5.5 MeV alpha particles was ~9%, which is comparable to that obtained in the XENON100 TPC with PMTs. The results are discussed within the context of potential GPM deployment in future multi-ton noble-liquid detectors.Comment: Submitted to JINS