The Development of Organelle Specific Hsp90 Isoform-Selective Inhibitors

项目摘要 90 kDa的热休克蛋白（Hsp 90）是负责约200个成熟的分子伴侣。 蛋白质底物（客户）。这些客户蛋白中的许多参与细胞信号传导途径， 调节细胞存活和增殖。抑制Hsp 90代表了一种有吸引力的方法， 由于大量依赖于Hsp 90的重要蛋白质， 提供了同时抑制多种致癌信号通路的独特机会。有四 Hsp 90同种型，都具有不同的客户蛋白亚组。每种同种型的选择性抑制是期望的， 减少受影响的客户蛋白质的数量并降低毒性风险。细胞器的发育 提出了一种特异性Hsp 90亚型选择性抑制剂，以阐明哪些客户蛋白是依赖于 并确定哪些类型的癌症严重依赖于每个子集。内质 网织膜定位同种型（Grp 94）负责与细胞运动相关的蛋白质的成熟， 具有减少癌症转移的用途。转移是癌症相关疾病的主要原因之一， 死亡，因为每一个新的转移性病变导致更差的预后。Grp 94的抑制提供了 有机会选择性地抑制癌症转移而不产生任何毒性，因为Grp 94是非- 对细胞存活至关重要。因此，Grp 94选择性抑制提供了减少转移的新方法 改善患者预后。同样，线粒体的异构体选择性抑制剂的开发 定位的Hsp 90同种型（Trap 1）。Trap 1的一个客户端（B-Raf）通常突变为组成型突变。 活性形式提供了侵袭性黑素瘤背后的驱动力。B-Raf抑制剂已被批准 然而，根据FDA，耐药性通常是通过使这些B-Raf抑制剂无效的突变而发生的。 Trap 1选择性抑制将降低B-Raf和突变体B-Raf的水平，从而减少 抵抗这种侵袭性的癌症。细胞器特异性Hsp 90亚型选择性抑制剂提供了新的 以及抑制侵袭性癌症进展的独特治疗选择。

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.