Single Agents with Designed Combination Chemotherapy Potential

针对受体酪氨酸激酶（RTK）的分子靶向药物，特别是抗血管生成药物（AAs），已经引起了癌症化疗的范式转变。这些药物靶向肿瘤血管生成机制（新血管的萌发），这些机制在正常细胞（伤口愈合、月经周期和妊娠除外）中不存在，但对肿瘤生长和转移至关重要。血管生成途径是冗余的，多靶向AAs是消除血管生成所必需的。AAs主要是细胞抑制剂和阻止肿瘤生长，但不杀死肿瘤。因此，原子吸收剂和细胞毒性药物的组合已显示出显著的前景，数百个这样的临床试验证明了它们的临床相关性。两种或多种药物的药代动力学差异、药物-药物相互作用、重叠毒性、多种药物的成本和患者依从性是联合化疗失败的重要方面。对于原子吸收剂与细胞毒性制剂的结合，则有更严格的要求。一些重要的抗血管生成作用，如肿瘤血管正常化是短暂的，单独给药的细胞毒性药物可能完全错过这个短暂的窗口期。联合化疗并不是一个新想法，新颖的是设计一种既具有多种抗血管生成活性又具有细胞毒性的单一药物。这种单一药物可以避免两种或多种单独药物的缺点，并在单分子中提供联合化疗的潜力。这种“现场”单一药物的细胞毒性作用将在抗血管生成作用的指示下表现出来，因此不需要定时或像单独施用的细胞毒性药物那样有效（因此毒性更小）。我们最近发现了两种化合物AAG14843和AAG148311，它们分别抑制VEGFR-2和PDGFR-$（肿瘤血管生成作用），并显著抑制人胸腺苷酸合成酶（hTS）（细胞毒性作用）。抑制能力

Molecularly targeted agents against receptor tyrosine kinases (RTK), particularly the antiangiogenic agents (AAs), have caused a paradigm shift in cancer chemotherapy. These agents target tumor angiogenic mechanisms (sprouting of new blood vessels) that are absent in normal cells (except wound healing, menstrual cycle and pregnancy) but are vital for tumor growth and metastases. Angiogenesis pathways are redundant and multi-targeted AAs are necessary to abrogate angiogenesis. AAs are mainly cytostatic and arrest tumor growth but do not kill tumors. Thus combinations of AAs and cytotoxic agents have shown significant promise, and hundreds of such clinical trials attest to their clinical relevance. Pharmacokinetic differences of two or more drugs, drug-drug interactions, overlapping toxicities, cost of multiple drugs and patient compliance are important facets of combination chemotherapy failure. For AAs in combination with cytotoxic agents there are even more stringent requirements. Some important antiangiogenic effects like tumor vascular normalization are transiently manifested and a separately administered cytotoxic agent might completely miss this transient window. Combination chemotherapy is not a new idea, what would be novel is the design of a single agent with both multiple antiangiogenic activities as well as cytotoxicity. Such single agents would circumvent the disadvantages of two or more separate agents and afford combination chemotherapy potential in single molecules. The cytotoxic effects of such “on the spot” single agents would be manifested when dictated by the antiangiogenic effects and hence would not need to be timed or be as potent (hence less toxic) as separately administered cytotoxic agents. We have recently discovered two compounds AAG14843 and AAG148311 that each inhibit VEGFR-2 and PDGFR-$, (tumor angiogenic effects) and remarkably also inhibit human thymidylate synthase (hTS) (cytotoxic effects). The inhibitory potencies are comparable to standard inhibitors of VEGFR-2 (SU5416), PDGFR-$ (DMBI) and hTS (pemetrexed, Alimta). In a COLO-205 xenograft mouse model AAG14843 significantly decreased tumor growth, liver metastases and blood vessels in the primary tumor compared to control. The Specific Aims are: 1.) to synthesize analogs of AAG14843 and AAG148311 to provide a structure-activity relationship (SAR) study, 3D QSAR and to optimize inhibitory activity against VEGFR-2, PDGFR-$ and hTS and antitumor activity. 2.) To test analogs from Specific Aim 1 against EGFR, VEGFR-1 and 2, PDGFR-$, P13K, FLT3, A431 cells, hDHFR, hTS and in the CAM assay. 3.) To evaluate in vivo toxicity, antitumor activity, metastases and antiangiogenic activity of AAG14843 (in other xenograft models), AAG148311 and three additional analogs identified from Specific Aims 1 and 2 in tumor mouse models. This study will afford a SAR and agents with optimized attributes of AAG14843 and allow the selection of agents to be developed for monotherapy, in combination with other agents and/or radiation for clinical use with greater efficacy and reduced toxicity than combinations currently in use.