Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors.
Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors.
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发表时间：
2000-10
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通讯作者：
E. Buchdunger;C. Cioffi;N. M. Law;D. Stover;Sayuri Ohno-Jones;B. Druker;N. Lydon
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作者：
E. Buchdunger;C. Cioffi;N. M. Law;D. Stover;Sayuri Ohno-Jones;B. Druker;N. Lydon
STI571（以前称为 CGP 57148B）是一种蛋白酪氨酸激酶抑制剂，目前正在进行治疗慢性粒细胞白血病的临床试验。 STI571 在体外选择性抑制 Abl 和血小板衍生生长因子 (PDGF) 受体酪氨酸激酶，并阻断 Bcr-abl 或 v-abl 表达细胞的细胞增殖和肿瘤生长。我们进一步研究了 STI571 针对相关受体酪氨酸激酶的特性。研究发现 STI571 可有效抑制 α- 和 β-PDGF 受体以及干细胞因子受体的激酶活性，但不抑制密切相关的 c-Fms、Flt-3、Kdr、Flt-1 和 Tek 酪氨酸激酶。此外，未观察到对 c-Met 或非受体酪氨酸激酶（例如 Src 和 Jak-2）的抑制作用。在基于细胞的检测中，STI571选择性抑制PDGF和干细胞因子介导的细胞信号传导，包括配体刺激的受体自身磷酸化、磷酸肌醇形成以及丝裂原激活的蛋白激酶激活和增殖。这些结果扩展了STI571的概况，并表明除了慢性粒细胞白血病之外，STI571可能在治疗涉及c-Kit或PDGF受体酪氨酸激酶异常激活的疾病方面具有临床潜力。
STI571 (formerly known as CGP 57148B) is a protein-tyrosine kinase inhibitor that is currently in clinical trials for the treatment of chronic myelogenous leukemia. STI571 selectively inhibits the Abl and platelet-derived growth factor (PDGF) receptor tyrosine kinases in vitro and blocks cellular proliferation and tumor growth of Bcr-abl- or v-abl-expressing cells. We have further investigated the profile of STI571 against related receptor tyrosine kinases. STI571 was found to potently inhibit the kinase activity of the alpha- and beta-PDGF receptors and the receptor for stem cell factor, but not the closely related c-Fms, Flt-3, Kdr, Flt-1, and Tek tyrosine kinases. Additionally, no inhibition of c-Met or nonreceptor tyrosine kinases such as Src and Jak-2 has been observed. In cell-based assays, STI571 selectively inhibited PDGF and stem cell factor-mediated cellular signaling, including ligand-stimulated receptor autophosphorylation, inositol phosphate formation, and mitogen-activated protein kinase activation and proliferation. These results expand the profile of STI571 and suggest that in addition to chronic myelogenous leukemia, STI571 may have clinical potential in the treatment of diseases that involve abnormal activation of c-Kit or PDGF receptor tyrosine kinases.