INSERM, U891, Centre de Recherche en Cancérologie de Marseille, Signalisation, Hematopoiesis and Mechanisms of Oncogenesis, Centre de référence des mastocytoses, Marseille, France.
PLoS One. 2009 Sep 30;4(9):e7258. doi: 10.1371/journal.pone.0007258.
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 (IC(50)) of 200+/-40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC(50) 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.
Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicity.
干细胞因子受体 KIT 是癌症、肥大细胞增多症和炎症性疾病治疗的靶标。在这里，我们描述了马替尼（AB1010）的体外和体内特性，这是一种新型的苯氨基噻唑型酪氨酸激酶抑制剂，针对 KIT。
方法/主要发现：在体外，马替尼对 KIT 的活性和选择性大于伊马替尼，对重组人野生型 KIT 的半抑制浓度（IC50）为 200+/-40 nM，并以 150+/-80 nM 的 IC50 阻断干细胞因子诱导的增殖和 KIT 酪氨酸磷酸化在表达人或鼠野生型 KIT 的 Ba/F3 细胞中。马替尼还能有效抑制重组 PDGFR 和细胞内激酶 Lyn，并在较小程度上抑制成纤维细胞生长因子受体 3。相比之下，马替尼对 ABL 和 c-Fms 的抑制作用较弱，对多种其他酪氨酸和丝氨酸/苏氨酸激酶无活性。马替尼的这种高度选择性表明它将比其他酪氨酸激酶抑制剂具有更好的安全性；事实上，在动物研究中没有观察到马替尼引起的心脏毒性或遗传毒性。分子建模和动力学分析表明，它与伊马替尼的结合方式不同，并且马替尼比伊马替尼更强烈地抑制脱颗粒、细胞因子产生和骨髓肥大细胞迁移。此外，马替尼强烈抑制了具有膜内 KIT 突变的人类和鼠类 KIT。在体内，马替尼阻断了表达膜内 KIT 突变体的 Ba/F3 细胞皮下移植瘤的生长。
马替尼是一种针对 KIT 的有效、选择性的酪氨酸激酶抑制剂，具有口服生物利用度，体内毒性低。
