A PHASE 1 SAFETY AND PHARMACOKINETIC STUDY OF SU011248 AND CAPECITABINE IN PA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。受体酪氨酸激酶（RTKs）是一种包含细胞外配体结合域和细胞内催化域的跨膜蛋白。RTKs在与其同源配体结合后被激活，许多涉及肿瘤生长、进展和转移的过程都是由这些蛋白下游的信号分子介导的[1,2]。RTKs分裂激酶结构域家族的几个成员与实体和血液肿瘤细胞的去调控/自分泌增殖和存活有关。这些包括血小板衍生生长因子受体（PDGFR和）；血管内皮生长因子受体（VEGFR） 1型和2型（FLT1和flk1 /KDR）；干细胞因子受体KIT；以及flt3配体受体。此外，rtk - PDGFR和VEGFR与肿瘤依赖性血管生成有关。SU011248是分子式为C22H27FN4O2的小分子。游离碱的分子量为398.48，而l -苹果酸盐是临床试验中使用的形式(错误！)，分子量为532.57。l-苹果酸盐的化学名称是5-（5-氟-2-氧-1,2-二氢吲哚-3-基乙基）-2,4-二甲基吡咯-3-羧酸（2-二乙基氨基乙基）-酰胺，与(S)-2-羟基琥珀酸1:1的化合物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Receptor tyrosine kinases (RTKs) are transmembrane proteins containing extracellular ligand-binding domains and intracellular catalytic domains. RTKs are activated following binding of their cognate ligands and many of the processes involved in tumor growth, progression and metastases are mediated by signaling molecules acting downstream from these proteins [1, 2]. Several members of the split-kinase domain family of RTKs are implicated in deregulated/autocrine proliferation and survival of solid and hematologic cancer cells. These include the platelet-derived growth factor receptors (PDGFR and ); vascular endothelial growth factor receptors (VEGFR) Type 1 and 2 (FLT1 and FLK 1/KDR); the stem cell factor (SCF) receptor, KIT; and the FLT3-ligand receptor. In addition RTKs PDGFR and VEGFR are implicated in tumor-dependent angiogenesis. SU011248 is a small molecule with the molecular formula C22H27FN4O2. The free base has a molecular weight of 398.48 and the L-malate salt, the form used in clinical trials (Error! Reference source not found.), has a molecular weight of 532.57. The chemical name of the L-malate salt is 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethylpyrrole-3-carbo ylic acid (2-diethylamino-ethyl)-amide, compound with (S)-2-hydroxy-succinic acid 1:1.