Identification of Novel, Drug-like Inhibitors of Hsp90

描述（由申请人提供）：尽管最近在癌症治疗方面取得了进展，但对新型抗癌治疗剂的鉴定仍然是迫切需要的。热休克蛋白90（Hsp 90）是一种分子伴侣，其结合并折叠几种客户蛋白，包括许多关键的癌症相关靶点，如激酶Bcr-Abl、Raf-1和SRC家族激酶如SRC、LCK和FYN，突变的p53、ErbB 2和类固醇激素受体。通过Hsp 90抑制破坏折叠过程导致这些客户蛋白的降解。由于Hsp 90客户蛋白在对癌细胞的生长和存活至关重要的过程中如此重要（例如，信号转导和转录中），Hsp 90抑制剂可用作针对许多癌症的有效化疗剂。这一假设已经通过格尔德霉素类似物17- AAG和17-DMAG在临床上得到验证。然而，这些安莎霉素类似物具有不良的药代动力学性质和脱靶毒性。因此，需要改进的Hsp 90抑制剂。该第一阶段提案的重点是使用Locus创新的计算技术设计的四种新型系列Hsp 90抑制剂的合成，生物评估和晶体学。这项研究的最终产品是一种口服的靶向Hsp 90的癌症治疗药物。

DESCRIPTION (provided by applicant): Despite recent advances in cancer treatment, the identification of novel anti-cancer therapeutic agents remains a pressing need. Heat Shock Protein 90 (Hsp90) is a molecular chaperone which binds to and folds several client proteins including a number of key cancer-relevant targets such as the kinases Bcr-Abl, Raf-1, and SRC family kinases such as SRC, LCK and FYN, mutated p53, ErbB2, and the steroid hormone receptors. Disruption of the folding process by Hsp90 inhibition leads to degradation of these client proteins. Because Hsp90 client proteins are so important in processes critical to the growth and survival of cancer cells (e.g., signal transduction and in transcription), Hsp90 inhibitors may serve as effective chemotherapeutic agents against a number of cancers. This hypothesis has been clinically validated by the geldanamycin analogs 17- AAG, and 17-DMAG. However, these ansamycin analogs suffer from poor pharmacokinetic properties and off- target toxicity. Thus, there is a need for improved Hsp90 inhibitors. This Phase I proposal focuses on synthesis, biological assessment and crystallography of four novel series of Hsp90 inhibitors that were designed using Locus' innovative computational technology. The ultimate proposed product of this research is an orally administered cancer therapeutic drug targeting Hsp90.