The Development of Organelle Specific Hsp90 Isoform-Selective Inhibitors

项目摘要 90 kDa热休克蛋白(Hsp90)是一种伴侣蛋白，负责大约200 蛋白质底物(客户)。这些客户蛋白中的许多都参与了细胞信号通路，这些信号通路对 调节细胞的存活和增殖。抑制Hsp90是一种有吸引力的方法 依赖于Hsp90的大量重要蛋白质引起的抗癌治疗研究进展 为同时抑制多种致癌信号通路提供了独特的机会。一共有四个 HSP90亚型，都有不同的客户蛋白子集。对每种异构体的选择性抑制是理想的 减少受影响的客户蛋白质的数量，降低毒性风险。细胞器的发育 为了阐明哪些客户蛋白是依赖的，提出了特定的hsp90异构体选择性抑制物。 根据这些亚型，确定哪些类型的癌症严重依赖于每个亚组。内质网 网状定位异构体(Grp94)负责与细胞运动性相关的蛋白质的成熟， 在减少癌症转移方面有应用。转移是导致癌症的主要原因之一。 死亡，因为每一个新的转移灶都会导致更糟糕的预后。对Grp94的抑制提供了 有机会选择性地抑制癌症转移而不会产生任何毒性，因为Grp94是非 对细胞生存至关重要。因此，Grp94选择性抑制为减少转移提供了一种新的途径 改善患者预后。同样，线粒体的异构体选择性抑制物的发展 将寻求本地化的Hsp90亚型(TRap1)。TRap1的一个客户(B-Raf)经常发生结构性突变 积极的形式提供了侵袭性黑色素瘤背后的驱动力。B-Raf的抑制剂已被批准 然而，FDA经常通过突变使这些B-Raf抑制剂无效而产生耐药性。 TRap1的选择性抑制将降低B-Raf和突变体B-Raf的水平，从而减少 这种侵袭性癌症的抗药性。细胞器特异性Hsp90异构体选择性抑制剂提供新的 和独特的治疗选择，以抑制侵袭性癌症的进展。

Project Summary The 90 kDa heat shock proteins (Hsp90) are chaperones responsible for the maturation of approximately 200 protein substrates (clients). Many of these client proteins are involved in cellular signaling pathways essential to regulating cell survival and proliferation. Inhibition of Hsp90 represents an attractive approach for the development of anticancer therapeutics due to the large number of important proteins dependent upon Hsp90 providing the unique opportunity to simultaneously inhibit multiple oncogenic signaling pathways. There are four Hsp90 isoforms, all with different a subset of client proteins. Selective inhibition of each isoform is desirable to reduce the number of client proteins affected and reducing the risk of toxicities. The development of organelle specific Hsp90 isoform-selective inhibitors is proposed in order to elucidate which client proteins are dependent upon these isoforms and determine which types of cancer rely heavily upon each subset. The endoplasmic reticulum localized isoform (Grp94) is responsible for the maturation of proteins associated with cell motility which has applications toward decreasing cancer metastasis. Metastasis is one of the leading causes of cancer related deaths because each new metastatic lesion leads to a worse prognosis. Inhibition of Grp94 provides the opportunity to selectively inhibit cancer metastasis without producing any toxicities due to Grp94 being non- essential to cell survival. Thus, Grp94-selective inhibition providing a novel approach to decreasing metastasis and improving patient prognosis. Similarly, the development of isoform-selective inhibitors of the mitochondria localized Hsp90 isoform (Trap1) will be pursued. One client of Trap1 (B-Raf) is often mutated to a constitutively active form providing the driving force behind aggressive melanomas. Inhibitors of B-Raf have been approved by the FDA, however, resistance often occurs through mutations rendering these B-Raf inhibitors ineffective. Trap1-selective inhibition will decrease levels of both B-Raf and mutant B-Raf reducing the occurrence of resistance in this aggressive form of cancer. Organelle specific Hsp90 isoform-selective inhibitor provide novel and unique therapeutic options to inhibit the progression of progression of aggressive cancers.