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.
Current Hsp90 inhibitors under clinical evaluation have proved to manifest toxicities which has slowed their development. Alternative strategies for Hsp90 inhibition are needed to overcome these deleterious attributes while maintaining efficacy against cancer. The goal of this proposal is to develop Hsp90 isoform-selective inhibitors to target specific types of cancer and reduce the toxic liabilities associated with current Hsp90 inhibitors.
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|Que, Nanette L S; Crowley, Vincent M; Duerfeldt, Adam S et al. (2018) Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding. J Med Chem 61:2793-2805|