Inhibition of Heat Shock Protein 90 Machinery for the Treatment of Cancer: Progress in the Development of Alternative Strategies

Abstract

Heat shock proteins (Hsps) are molecular chaperones that facilitate the conformational maturation of newly synthesized and unfolded cellular proteins (termed “clients”) to maintain protein homeostasis. Heat shock protein 90 (Hsp90) is a chaperone that folds client substrates, many of which drive signal transduction pathways associated with cellular proliferation and differentiation. Consequently, Hsp90 can facilitate oncogenic transformation and can sustain the proper functioning of signaling pathways that have been hijacked during cancer formation and progression. Hsp90 functions as a homodimer and facilitates client maturation via the Hsp90 chaperone cycle. During this cycle, Hsp90 forms a heteroprotein complex with additional proteins (e.g., co-chaperones, partner proteins, immunophilins, etc.) that assist in client folding at different stages of the cycle. However, if this cycle is disrupted and a client is unable to reach conformational maturity, the immature client is ubiquitinylated and degraded via the proteasome. Given Hsp90’s role in cancer progression, Hsp90 inhibition has emerged as a viable strategy for the development of anticancer chemotherapeutics. Classic Hsp90 inhibitors compete with ATP at the Hsp90 N-terminus, of which ATP-binding and hydrolysis is crucial for client maturation. However, these N-terminal inhibitors lead to induction of the pro-survival heat shock response via activation of the transcription factor, heat shock factor-1 (HSF-1; resides at the Hsp90 N-terminus). HSF-1 activation ultimately increases the cellular concentration of Hsps, including Hsp90. Therefore, alternative strategies to inhibit Hsp90 function and/or client maturation that avoid HSF-1 activation (i. e. increased Hsp90 levels) have been pursued. An alternative strategy to inhibit Hsp90-dependent client maturation is to target the Hsp90 C-terminus. The natural products novobiocin and (-)-epigallocatechin-3-gallate (EGCG) were previously identified as Hsp90 C-terminal inhibitors and provide platforms for elucidation of structure-activity relationship studies for the Hsp90 C-terminus. These natural products led to development of analogs that exhibited potent anti-proliferative activity across several different cancer cell lines, many of which decreased the cellular levels of Hsp90 clients and did not affect Hsp levels. Another strategy to prevent Hsp90 client maturation is to disrupt components of the heteroprotein complex, specifically the interactions between Hsp90 and its co-chaperones. The known F1F0 ATP synthase inhibitor, cruentaren A, was shown to disrupt interactions between the co-chaperone F1F0 ATP synthase and Hsp90 via F1F0 ATP synthase inhibition. Disruption of this interaction led to decreased client levels and no increase in Hsp levels. Other disruptors of Hsp90 client maturation include members of the cucurbitacin class of natural products, specifically cucurbitacin D and 3-epi-isocucurbitacin D. These cucurbitacins led to decreased client protein levels without HSF-1 activation. However, only cucurbitacin D disrupted interactions between Hsp90 and the co-chaperones, Cdc37 and p23, similar to the known heteroprotein complex disruptor, gedunin.