Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy

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The Hsp90 chaperone is a master regulator of the stability and activity of multiple oncoproteins such as Her2, Akt, Bcr-Abl, c-Kit, EGFR and mutant BRAF. The promise of inhibition of such a master regulator for cancer therapy is the potential to cause combinatorial inhibition of multiple oncogenic signaling pathways simultaneously. With the recent discovery of feedback loops that effectively negate the efficacy of selectively targeted anti-cancer agents, there is renewed interest in such a multi-pronged approach. There are now 14 drug candidates that target Hsp90 undergoing clinical trials in multiple indications as single agents or combination therapy. These compounds represent a diverse array of chemical matter stemming from natural product scaffolds to synthetic structure-based design. Although the compounds fall into distinct classes with unique properties, each inhibitor binds in the N-terminal ATP pocket and accumulates in tumor tissue while being rapidly cleared from circulation and normal tissue. The most advanced candidates are now in Phase 2 clinical trials and defining the therapeutic window, dosing schedule, and indication are the primary challenges for these potential first-in-class inhibitors.

Introduction

Activation of the heat shock response is a general property of cancer cells involved in the initiation as well as the maintenance of the transformed phenotype [1]. A particularly important component in the heat shock response is heat shock protein 90 (Hsp90), a molecular chaperone that uses repeated cycles of client protein binding and ATP hydrolysis to modulate the stability and activity of its client proteins [2]. In contrast to ‘early’ chaperones (Hsp70, NAC, TRiC), Hsp90 is not involved in the folding of nascent polypeptides as they emerge from the ribosome, rather, it seems to control aspects of activity, stability, and protein sorting [3]. The ubiquitin ligase CHIP is part of the Hsp90 complex, explaining how upon inhibition of Hsp90, proteins are actively targeted to the proteasome and degraded [4]. Only a small percentage of all proteins in the cell (about 200) are known Hsp90 client proteins and they are almost exclusively signaling proteins like kinases and transcription factors. Consistent with the role of an activated heat shock response in cancer, Hsp90 is over-expressed in cancer cells and correlated with disease progression in melanoma [5] and associated with decreased survival in breast cancer, gastrointestinal stromal tumors (GIST), and non-small cell lung cancer (NSCLC) [6•, 7, 8].

Hsp90 inhibition has attracted considerable interest in the past two decades for the treatment of advanced cancers. In general, Hsp90 inhibitors display remarkable selectivity for cancer cells as compared to normal cells [9] and the inhibitors have been shown to accumulate in tumor tissue while being rapidly cleared from circulation and normal tissue. Inhibition of Hsp90 has the potential to shut down multiple oncogenic signaling pathways simultaneously [10]. This approach might be particularly relevant with the recent discovery of feedback loops that counteract the efficacy of molecularly targeted agents. For example, inhibition of mTOR activates upstream Akt and parallel MAPK signaling [11, 12], negating the effects of mTOR inhibitors. In tumors with activated receptor tyrosine kinases, inhibitors of the kinase activity of mitogen-activated protein kinase (MEK) lead to an increase in activated MEK [13], again limiting the effectiveness of these inhibitors in such tumors. One solution to combat feedback loops, is to attack cancers with a multimodal inhibitor that simultaneously inhibits multiple signaling nodes. Hsp90 inhibitors appear uniquely suited for this purpose.

Another area of distinct applicability of Hsp90 inhibitors is their use to combat the emergence of resistance mutations. Resistance to targeted agents often arises through secondary mutations in the target protein that preclude the small molecule from binding to its target oncoprotein. Many of these oncoproteins depend on Hsp90 to maintain their activated oncogenic state; additional mutations (to evade small molecule binding) can make these proteins even more dependent on the Hsp90 chaperone. Towards this end, the therapeutic potential of Hsp90 inhibition has been evaluated extensively and to date, 14 unique chemical moieties have entered clinical trials as potential cancer therapeutics.

Section snippets

Benzoquinone, hydroquinone, and phenol ansamycins

The fundamental understanding of Hsp90 inhibition has been investigated thoroughly with the ansamycin natural product class (Figure 1). A landmark publication by Whitesell and Neckers in 1994 [14] described the inhibition of the formation of a src-Hsp90 heteroprotein complex both in reticulocyte lysate and intact cells upon treatment with the natural product geldanamycin (1) [15]. Subsequent co-crystal structure determination of Hsp90 complexed to geldanamycin identified that the compound

Conclusions

There are 14 Hsp90 inhibitors in various stages of clinical development as both IV and oral therapeutics (see Table 1, Table 2). The most advanced product candidates are 17-AAG in a Phase 3 trial in combination with bortezomib in a first-relapsed patient population for the treatment of multiple myeloma (Bristol Myers Squibb), IPI-504 (Infinity) in Phase 2 trials in patients with Her2-positive metastatic breast cancer and NSCLC, BIIB021 (Biogen-Idec) in Phase 2 trials in breast and GIST,

Conflict of interest

The authors are employees and stock holders of Infinity Pharmaceuticals, Inc.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest.

Acknowledgement

The authors would like to thank the Hsp90 project team at Infinity Pharmaceuticals Inc.

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