HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review)

Abstract

Heat shock protein 90 (HSP90) is a vital chaperone protein, regulating signaling pathways and correcting misfolded proteins in cancer cells by interacting with oncogenic client proteins and co-chaperones. The inhibition of HSP90 chaperone machinery has been demonstrated as a potential approach with which to inhibit tumor survival, proliferation, invasion and migration. Numerous HSP90 inhibitors have been reported and have exhibited value as cancer-targeted therapies by interrupting the ATPase activity of HSP90, thus suppressing the oncogenic pathways in cancer cells. These inhibitors have been classified into three categories: i) N-terminal domain (NTD) inhibitors; ii) C-terminal domain (CTD) inhibitors; and iii) isoform-selective inhibitors. However, none of these HSP90 inhibitors are used as clinical treatments. The major limiting factors can be summarized into drug resistance, dose-limiting toxicity and poor pharmacokinetic profiles. Novel HSP90-targeted compounds are constantly being discovered and tested for their antitumor efficacy in preclinical and clinical trials, highlighting the prospect of the use of HSP90 inhibitors as cancer-targeted therapies. Additionally, improved antitumor effects have been observed when HSP90 inhibitors are used in combination with chemotherapy, targeted agents, or immunotherapy. In the present review, the effects of HSP90 inhibitors on the management of the cancer process are discussed and previous and novel HSP90-based therapeutic strategies in cancer treatment are summarized. Furthermore, prospective HSP90-targeting candidates are proposed for their future evaluation as cancer treatments. Contents 1. Introduction 2. Structure and biological function of HSP90 3. HSP90 as a druggable target in cancer therapy 4. Old and new anti-neoplastic treatments targeting HSP90 5. Conclusions and future perspectives

Synthesis and Experimental Structure of a Multifunctional Catechol‐Azomethinebenzoic Acid, DFT/DMol3Calculations, and Molecular Docking with Hsp90

“…They are hydrophobic in nature, confirming that the catechol hydroxy functions were strongly engaged in intramolecular hydrogen bond interactions, leaving an overall hydrophobic character of this unit. With this, the catechol unit stands in contrast to the m ‐dihydroxy configuration of resorcinol‐moieties, which is a frequent motives Hsp90 inhibitors, such as in radicicol [37,39,40,42] . These interactions were completed by further multiple hydrophobic … hydrophobic interactions of 1 with the active site (Asn40, Ala44, Ile85, Met87, Asn95, Leu96, Arg101, Gly125, Gly127, Tyr129, and Thr174), which are in line with the Hirshfeld surface analysis showing huge areas in which hydrophobic H … H contacts govern the intermolecular interactions.…”

“…One of them, the so-called Bergerat fold is a unique adenine-nucleotide-binding pocket found in the N-terminal domain with the chaperon activity of Hsp90 being dependent on an ATPase cycle. [36,37] . Hsp90 inhibitors such as geldanamycin (G, Scheme 1, left), 7-allylaminogeldanamycin (17-AAG), and radicicol, bind to this ATP site inhibiting the ATPase activity.…”

“…[31,33] Many different small chemical inhibitors targeting Hsp90 have been described [31][32][33][34][35] and are at present in clinical trials including geldanamycin derivatives, purine-based molecules, benzamides such as SNX-5422, resorcinol(benzene-1,3-diol)-based structures, but also molecules which do not follow established structure-activity relations. [37][38][39][40][41][42] This wealth of structures clearly calls for in silico screening using molecular docking approaches. [39,[42][43][44][45][46][47][48] Herein we report a new multifunctional potential inhibitor molecule based on a catechol-azomethine-benzoic acid template, 4-[(E)-[(2,3-dihydroxyphenyl)methylidene]amino]benzoic acid (1) (Scheme 1, right) synthesized from 2,3-dihydroxybenzaldehyde and 4-aminobenzoic acid.…”

“…Hsp90 is made up of three flexible domains. One of them, the so‐called Bergerat fold is a unique adenine‐nucleotide‐binding pocket found in the N ‐terminal domain with the chaperon activity of Hsp90 being dependent on an ATPase cycle [36,37] …”

“…They also stop the client protein from separating from the Hsp90 complex [31,33] . Many different small chemical inhibitors targeting Hsp90 have been described [31–35] and are at present in clinical trials including geldanamycin derivatives, purine‐based molecules, benzamides such as SNX‐5422, resorcinol(benzene‐1,3‐diol)‐based structures, but also molecules which do not follow established structure‐activity relations [37–42] . This wealth of structures clearly calls for in silico screening using molecular docking approaches [39,42–48] …”