Mechanism of Action by mTOR Kinase Inhibitors in Colorectal Cancer

描述（由申请人提供）：雷帕霉素靶蛋白（TOR）是一种保守的蛋白激酶，是细胞生长和存活的关键调节剂，作用于PI3K的下游。pi3k -哺乳动物/机械性TOR （mTOR）通路在人类癌症中经常超激活，导致癌症生长不受控制，是癌症药物的主要靶点。mTOR形成两种不同的多聚蛋白复合物，mTORC1和mTORC2，它们都是癌细胞生长、增殖和存活所必需的。大环内酯类雷帕霉素和雷帕霉素类似物（rapalogs）是部分mTOR抑制剂，对主要人类癌症的疗效有限。最近，mTOR激酶抑制剂（mTKIs）已成为第二代mTOR靶向治疗药物。早期研究表明，mTKIs确实对几种雷帕霉素耐药肿瘤模型有效。因此，大量的mTKIs迅速进入人体临床试验。从最初的药物发现到人体临床试验的非凡速度强调了这类新型抗肿瘤药物的治疗潜力。尽管取得了早期进展，但仍存在重大挑战。到目前为止，对其作用机制的研究还很少。作为atp竞争性抑制剂，可能存在“脱靶”效应

DESCRIPTION (provided by applicant): Target of rapamycin (TOR) is a conserved protein kinase and a key regulator of cell growth and survival, acting downstream of PI3K. PI3K-mammalian/mechanistic TOR (mTOR) pathway is frequently hyper-activated in human cancers, leading to uncontrolled cancer growth, which is a major cancer drug target. mTOR forms two distinct multimeric protein complexes, mTORC1 and mTORC2, both of which are required for cancer cell growth, proliferation and survival. The macrolide rapamycin and rapamycin analogs (rapalogs) are partial mTOR inhibitors with limited efficacy toward major human cancers. Recently, mTOR kinase inhibitors (mTKIs) have emerged as the second generation of mTOR-targeted therapeutics. Early studies showed that mTKIs are indeed effective against several rapamycin-resistant tumor models. As a result, a large number of mTKIs rapidly entered human clinical trials. The extraordinary speed from initial drug discovery to human clinical trials underscores the therapeutic potential of this class of new anti-neoplastic agents. Despite early progress, significant challenges remain. Thus far, there have been few studies on their mechanisms of action. As ATP-competitive inhibitors, there are likely to be "off-target" effect but this issue has not been carefully addressed. Moreover, there has been no reported study on intrinsic or acquired resistance to this new drug class. Our application is aimed at answering these critically important yet unaddressed questions. The rationale and feasibility of our research plan are strongly supported by the preliminary results. Successful completion of this project should have significant impact on the clinical development of this new class of anti-neoplastic agents.