Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahy dro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t(1/2) = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man.

中文翻译：

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N-（5-氯-1,3-苯并二恶唑-4-基）-7- [2-（4-甲基哌嗪-1-基）乙氧基] -5-（四氢-2H-吡喃-4-基氧基）喹唑啉- 4-胺，一种新型的，高选择性，口服可得的双特异性c-Src / Abl激酶抑制剂。

Src家族激酶（SFK）是非受体酪氨酸激酶，据报道对于癌症的进展至关重要。我们在这里报告了一个新的C-5取代的苯胺基喹唑啉亚型，对c-Src和Abl酶的酪氨酸激酶域显示出高亲和力和特异性。这些化合物在一系列重组蛋白激酶上对SFK具有高选择性，出色的药代动力学和口服给药后的体内活性。N-（5-氯-1,3-苯并二恶唑-4-基）-7- [2-（4-甲基哌嗪-1-基）乙氧基] -5-（四氢-2H-吡喃-4-基氧基）喹唑啉-4-胺（AZD0530）在低纳摩尔浓度下抑制c-Src和Abl酶，并且在一系列激酶中具有高度选择性。AZD0530在动物的临床前和人类中显示出出色的药代动力学参数（t（1/2）= 40 h）。AZD0530在体内经c-Src转染的3T3-成纤维细胞异种移植模型中是一种有效的肿瘤生长抑制剂，在每天口服一次的人胰腺癌高度侵袭性原位移植模型中，其存活率显着提高。AZD0530目前正在人体中进行临床评估。