Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90

Abstract

The benzoquinone ansamycin geldanamycin and its derivatives are inhibitors of heat shock protein Hsp90, an emerging target for novel therapeutic agents both in cancer and in neurodegeneration. However, toxicity of these compounds to normal cells has been ascribed to reaction with thiol nucleophiles at the quinone 19-position. We reasoned that blocking this position would ameliorate toxicity, and that it might also enforce a favourable conformational switch of the trans-amide group into the cis-form required for protein binding. We report here an efficient synthesis of such 19-substituted compounds and realization of our hypotheses. Protein crystallography established that the new compounds bind to Hsp90 with, as expected, a cis-amide conformation. Studies on Hsp90 inhibition in cells demonstrated the molecular signature of Hsp90 inhibitors: decreases in client proteins with compensatory increases in other heat shock proteins in both human breast cancer and dopaminergic neural cells, demonstrating their potential for use in the therapy of cancer or neurodegenerative diseases.

Heat shock protein 90 controls HIV-1 reactivation from latency

“…2). In agreement with these results, compounds with an extra group at position 19 have lower affinity for Hsp90 due to a structural clash at the edge of the ATPase pocket (22). We also tested AUY922, a small molecule inhibitor of Hsp90, currently in phase II clinical trials (19).…”

“…TPA, prostratin, geldanamycin, 17-(N-allylamino)-17-demethoxygeldanamycin (17-AAG), 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), were obtained from Sigma; Gö6976 and GF10920X from Calbiochem; U0126, AUY922, and sotrastaurin were obtained from Selleckchem; and SAHA was purchased from Cayman Chemical. The synthesis of 19-substituted geldanamycin derivatives was described previously (22,23). Compounds diluted in DMSO were stored at −80°C in the dark.…”

“…Notably, addition of a methyl or phenyl group at position 19 (22,23) made the compounds significantly weaker suppressors of HIV-1 reactivation (Fig. 2).…”

Role of Heat Shock Protein 90 in the Cause of Various Diseases: A Potential Therapeutic Target

“…A list of the inhibitors name and working system of HSP90-inhibitors in various neurodegeneration was given in tabular form in Table 14.1. Moreover, it is worthy to mention that Kitson and his group recently reported the synthesis of 19 GA substitute HSP90 inhibitors which exhibited much less toxicity and when tested in human breast cancer and dopaminergic neural cells, they demonstrated them to act as potential therapeutic agent against both cancer and dopaminergic cells [64].…”

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

“…Geldanamycin has since been shown to reduce toxicity of a-synuclein in several other model systems and in additional disease models (McLean et al 2004;Shen et al 2005;Waza et al 2005Waza et al , 2006Batulan et al 2006;Thomas et al 2006;Liu et al 2009). Derivatives of the ansamycin family are being generated to identify inhibitors with reduced inherent toxicity for future therapeutics (Kitson et al 2013).…”