Heat shock protein 90 (HSP90) inhibitors in gastrointestinal cancer: where do we currently stand?—A systematic review

Abstract

Purpose Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target in oncology, including the treatment of gastrointestinal cancers. Methods We carried out a systematic review of data extracted from clinicaltrials.gov and pubmed.gov, which included all studies available until January 1st, 2022. The published data was evaluated using primary and secondary endpoints, particularly with focus on overall survival, progression-free survival, and rate of stable disease. Results Twenty trials used HSP90 inhibitors in GI cancers, ranging from phase I to III clinical trials. Most studies assessed HSP90 inhibitors as a second line treatment. Seventeen of the 20 studies were performed prior to 2015 and only few studies have results pending. Several studies were terminated prematurely, due to insufficient efficacy or toxicity. Thus far, the data suggests that HSP90 inhibitor NVP-AUY922 might improve outcome for colorectal cancer and gastrointestinal stromal tumors. Conclusion It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade.

An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis

“…Importantly, XL888 attenuated multiple fibrotic indicators, including total collagen content, in the preclinical model of lung fibrosis. XL888 is currently in Phase I clinical trials as a potential anticancer agent in solid tumors ( 33 ), but our study would suggest a potential role in fibrotic diseases. While our screen was hypothesis-free, it was reassuring that we identified a compound class that has previously been shown to exhibit senolytic properties.…”

Expression and role of FKBPL in lung adenocarcinoma

“…Dysregulated expression of heat shock protein has been demonstrated to play crucial roles in tumour development. Heat shock proteins are reported to be involved in hallmarks of cancer, such as mitosis, and apoptosis 23 . Aberrant expression of HSP27 is associated with tumorigenesis and metastasis in various cancers.…”

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

“…[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.…”

“…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] …”