Protein chaperones: a composition of matter review (2008 – 2013)

Abstract

Introduction Heat shock proteins (Hsps) are proteins with important functions in regulating disease phenotypes. Historically, Hsp90 has first received recognition as a target in cancer, with consequent efforts extending its potential role to other diseases. Hsp70 has also attracted interest as a therapeutic target for its role as a co-chaperone to Hsp90 as well as its own anti-apoptotic roles. Areas covered Herein, patents from 2008 to 2013 are reviewed to identify those that disclose composition of matter claimed to inhibit Hsp90 or Hsp70. Expert opinion For Hsp90, there has been considerable creativity in the discovery of novel pharmacophores that fall outside the three initially discovered scaffolds (i.e., ansamycins, resorcinols and purines). Nonetheless, much of the patent literature appears to build on previously reported structure activity relationship through slight modifications of Hsp90 inhibitor space by finding weaknesses in existing patents. The major goal of future development of Hsp90 inhibitors is not necessarily identifying better molecules but rather understanding how to rationally use these agents in the clinic. The development of Hsp70 inhibitors has lagged behind. It will require a more concerted effort from the drug discovery community in order to begin to realize the potential of this target.

Effects of treatment with an Hsp90 inhibitor in tumors based on 15 phase II clinical trials

“…Loss of Hsp90 function leads to ubiquitination and degradation of these proteins, causing cell growth inhibition, apoptosis of tumor cells and antitumor activity in preclinical models (8)(9)(10)(11)(12). These preclinical observations have prompted the clinical assessment of Hsp90 inhibitors in various tumor types.…”

“…Accordingly, multiple mitogenic pathways may be inhibited by synthetic inhibitors of the Hsp90 ATPase activity, including 17-allylamino-17-demthoxygeldanamycin (17-AAG), ganetespib, retaspimycin HCl (IPI-504) and BIIB021 (3)(4)(5)(6)(7). Evidence of the activity of Hsp90 inhibitors was shown in vitro, and animal models of different types of tumor and numerous clinical trials were performed to search for novel treatments against tumors (8)(9)(10)(11)(12). The present study summarized 15 phase II clinical trials using Hsp90 inhibitors and found that the lack of efficacy of Hsp90 inhibitors in these initial phase II studies may be due to the treatment-associated toxicity limitation, accounting for insufficient dose of drug or infrequent schedule of administration, which in turn leads to inadequate inhibition of target proteins.…”

Proteotoxicity and Cardiac Dysfunction

“…41 Their many functional roles are underscored by changes they may undergo as a result of post-translational modification, 42 the potential for their trans-cellular activities 43 and the role they play in a wide variety diseases including but not limited to Pompe disease, Huntington disease, cancer, pulmonary and cardiovascular disease. 6,44-51 Not surprisingly, considering their role in these processes, targeting the chaperones has become a legitimate therapeutic avenue. 49,52 …”

Proteotoxicity and Cardiac Dysfunction

“…41 Their many functional roles are underscored by changes they may undergo as a result of post-translational modification, 42 the potential for their trans-cellular activities 43 and the role they play in a wide variety diseases including but not limited to Pompe disease, Huntington disease, cancer, pulmonary and cardiovascular disease. 6,[44][45][46][47][48][49][50][51] Not surprisingly, considering their role in these processes, targeting the chaperones has become a legitimate therapeutic avenue. 49,52 The HSR is the most evolutionarily ancient of the PQC pathways, enlisting molecular chaperones ( Figure 1, top panel), such as the HSPs, to manage two primary functions within the cell: transiently interact with nascent unfolded polypeptides to guide them towards their proper folded conformation and target terminally misfolded proteins for degradation.…”