Buchdunger E, Cioffi C L, Law N, Stover D, Ohno-Jones S, Druker B J, Lydon N B
Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland.
J Pharmacol Exp Ther. 2000 Oct;295(1):139-45.
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.
STI571（原名CGP 57148B）是一种蛋白酪氨酸激酶抑制剂，目前正处于治疗慢性粒细胞白血病的临床试验阶段。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，并阻断表达Bcr-abl或v-abl的细胞的细胞增殖和肿瘤生长。我们进一步研究了STI571对相关受体酪氨酸激酶的作用情况。发现STI571能有效抑制α-和β-PDGF受体以及干细胞因子受体的激酶活性，但对密切相关的c-Fms、Flt-3、Kdr、Flt-1和Tek酪氨酸激酶无抑制作用。此外，未观察到对c-Met或非受体酪氨酸激酶如Src和Jak-2的抑制作用。在基于细胞的试验中，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、肌醇磷酸形成、丝裂原活化蛋白激酶激活和增殖。这些结果扩展了STI571的作用情况，并表明除慢性粒细胞白血病外，STI571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可能具有临床潜力。
