Recent Advances in Macrocyclic Hsp90 Inhibitors

Abstract

Natural products were the first compounds to confirm the advantages of cyclised structures, where the ring conformation provides structural stability and chemical potency. Successful clinical applications of macrocyclic compounds in oncology have produced powerful incentives within the medicinal chemistry community to explore macrocyclic drug candidates that target novel oncogenic pathways. Numerous receptors, signalling molecules, and enzymes involved in oncogenesis require the chaperone activity of heat shock protein 90 (Hsp90), an ATPase-driven dimer whose chief molecular roles involve protein folding and stabilisation. Herein we describe four classes of macrocyclic Hsp90 inhibitors. Class I macrocyclic anticancer agents, currently in clinical trials, target the ATP-binding pocket of Hsp90 and include synthetic derivatives of the ansamycin antibiotic geldanamycin (17-AAG or tanespimycin, 17-DMAG or alvespimycin, IPI-504 or retaspimycin). Class II inhibitors (radicicol, radanamycin), which also target the ATP-binding pocket of Hsp90, demonstrate greater potency than Class I inhibitors in preclinical studies, and recent improvements incorporated into synthetic derivatives and chimeras have led to greater structural stability than class I without loss of potency. Class III features synthetic derivatives targeting Hsp90's ATPase activity (o-aminobenzamides and aminopyrimidines), with promising clinical data pointing to these scaffolds as the next generation of therapeutic Hsp90 inhibitors. Class IV compounds are allosteric inhibitors that bind to the N-middle domain of Hsp90 and block access to proteins that bind the C-terminus of Hsp90 (SM122 and SM145). This final class is unique as it does not target the ATP binding site of Hsp90, thereby avoiding induction of the heat shock response. Development of compounds that modulate Hsp90's C-terminus may prove to be an effective method of avoiding the rescue response mounted when blocking the ATP-ase activity of Hsp90.

Transition metal-catalyzed double Cvinyl–H bond activation: synthesis of conjugated dienes

“…Conjugated dienes and polyenes are one of the main building blocks in organic chemistry and represent fundamental structural motifs in a wide range of natural products as well as in bioactive molecules. 1 Some representative examples containing conjugated dienes are vitamin A, 2 lissoclinolide, 3 abscisic acid, 4 macrolactin A, 5 lactimidomycin, 6 modiolin, 7 etc . (Fig.…”

Heat-Shock Protein 90 Inhibitors: Will They Ever Succeed as Chemotherapeutics?

“…Several reasons appear to be responsible for 17-AAG's failure at clinical trials. First, 17-AAG is also known to target other ATP-binding sites including DNA polymerases, tyrosine kinases and multiple isoforms of mammalian Hsp90 protein (references within [19]). Second, the quinone has toxic properties.…”

“…Alternatives to 17-AAG have been developed [19], and several promising molecules, including AUY922 [5] and Ganetspib (STA-9090) [20], are in current clinical trials as monotherapies. However, there are still concerns about the HSR triggered by blocking the ATP-Hsp90 interaction, as it provides tumor cells an opportunity to survive.…”

Anti-influenza virus activity of benzo[d]thiazoles that target heat shock protein 90

“…After the discovery of the Hsp90 inhibitor geldanamycin, many other such inhibitors have been described, some of which have undergone phase III anticancer testing (Fig. 2) [45][46][47]. This includes: structural analogues of geldanamycin, such as alvespimycin (17-DMAG), tanespimycin (17-AAG) and retaspimycin (IPI-504); the macrolide compounds radicicol and ganetespib (STA9090); purine-based inhibitors such as Debio 0932; and the antibiotics novobiocin and coumermycin A1.…”