Chemically Accessible Hsp90 Inhibitor That Does Not Induce a Heat Shock Response

Abstract

Recent cancer therapies have focused on targeting biology networks through a single regulatory protein. Heat shock protein 90 (hsp90) is an ideal oncogenic target as it regulates over 400 client proteins and cochaperones. However, clinical inhibitors of hsp90 have had limited success; the primary reason being that they induce a heat shock response. We describe the synthesis and biological evaluation of a new hsp90 inhibitor, SM253. The previous generation on which SM253 is based (SM145) has poor overall synthetic yields, low solubility, and micromolar cytotoxicity. By comparison SM253 has relatively high overall yields, good aqueous solubility, and is more cytotoxic than its parent compound. Verification that hsp90 is SM253's target was accomplished using pull-down and protein folding assays. SM253 is superior to both SM145 and the clinical candidate 17-AAG as it decreases proteins related to the heat shock response by 2-fold, versus a 2-4-fold increase observed when cells are treated with 17-AAG.

Regulating the master regulator: Controlling heat shock factor 1 as a chemotherapy approach

“…33,53 Finally, a recent Letter shows that the non-classical Hsp90 inhibitor SM253 decreases HSF1 levels to 50% of background when used to treat HCT-116 colon cancer or MiaPaCa-2 pancreatic cancer cells. 54 In contrast, the classical inhibitor 17-AAG increased HSF1 protein levels by 3 fold. 54 A molecule just published by McAlpine and co-workers, SM258, is highly effective at inhibiting HSF1 levels when used at 10 fold over the IC 50 value, reducing HSF1 below detectable levels in treated cells.…”

“…54 In contrast, the classical inhibitor 17-AAG increased HSF1 protein levels by 3 fold. 54 A molecule just published by McAlpine and co-workers, SM258, is highly effective at inhibiting HSF1 levels when used at 10 fold over the IC 50 value, reducing HSF1 below detectable levels in treated cells. 28 In contrast treatment with 10 fold over the IC 50 of the classical inhibitor NVP-AUY-922 produced a 10 fold increase in HSF1 protein levels.…”

“…3a). [12][13][14][15][16]28,54 The induction of the HSR and elevated HSF1 promotes resistance. The classic Hsp90 inhibitors has been known to cause the HSR and increased HSF1 levels for the last 2 decades, however, the recent developments in the understanding of HSF1 and its integral part in cancer initiation highlights the need for other types of Hsp90 inhibitors.…”

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

“…These data indicate that the pyridyl moieties are detrimental to binding to Hsp90 regardless of the nitrogen location, but alternative heterocycles can provide effective binding affinity. Specifically SM249G showed high selectivity for Hsp90 (using pull-down assays), and the ability to inhibit binding between Hsp90 and its clients [35]. In addition, SM249G's solubility was significantly improved over SM249A, as was its ability to inhibit Hsp90 from refolding proteins.…”

“…3) from the D-Phe in SM249A to aromatic heterocycle moieties including pyridine, indole, p-substituted phenyl, and thiazole produced compounds SM249B-G, (Fig. 3) [35].…”