Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor
Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor
复制标题
DOI：
10.1158/1535-7163.mct-07-2232
复制
发表时间：
2008-07-01
影响因子：
5.7
通讯作者：
Vincent, Patrick W.
中科院分区：
文献类型：
--
作者：
Gonzales, Andrea J.;Hook, Kenneth E.;Vincent, Patrick W.
通过酪氨酸激酶的erbB受体家族的信号传导有助于多种细胞类型的增殖、分化、迁移和存活。该受体家族成员的脱落已被证明在肿瘤发生中起作用，从而使它们成为抗癌治疗的有吸引力的靶点。PF-00299804是目前处于I期临床试验的第二代不可逆pan-erbB受体酪氨酸激酶抑制剂。认为PF-00299804通过在ATP位点结合和erbB家族成员催化结构域中亲核半胱氨酸残基的共价修饰，不可逆地抑制erbB酪氨酸激酶活性。PF-00299804经口给药可引起显著的抗肿瘤活性，包括在表达和/或过表达erbB家族成员或在erbB 1（EGFR）中含有与吉非替尼和厄洛替尼耐药相关的双突变（L 858 R/T790 M）的多种人肿瘤异种移植模型中出现显著的肿瘤消退。此外，PF-00299804在人肿瘤异种移植物中的分布异常，在种属间具有优异的药代动力学特性。
Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species.