Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90–Kinase Interactions

Abstract

Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naïve and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.

Design, synthesis and pharmacological evaluation of 4,5-diarylisoxazols bearing amino acid residues within the 3-amido motif as potent heat shock protein 90 (Hsp90) inhibitors

“…Heat shock proteins (Hsps) are a family of molecular chaperones that consist of Hsp100, Hsp90, Hsp70, Hsp60 and many other smaller Hsps (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) [1,2].…”

“…Therefore, Hsp90 has long been recognized as a viable molecular target for cancer treatment [13]. The majority of Hsp90 inhibitors currently in the clinic are Hsp90 N-terminal inhibitors that interact with the ATPase binding site in the N-terminal of Hsp90 structure [14][15][16]. The earlier Hsp90 inhibitors including the natural product geldanamycin and its analogues (e.g.…”

The Association Between HSP90/topoisomerase I Immunophenotype and the Clinical Features of Colorectal Cancers in Respect to KRAS Gene Status

“…HSP90 is an important molecular chaperone for protein folding, transmission, and intracellular localization, in both normal and tumor cells (16,17). HSP90 is an important regulator of cell growth and survival, as well as being essential for the activity of a wide range of key oncogenic proteins, including kinases, transcription factors, and suppressor proteins (17,18). Many HSP90 client proteins are involved in processes such as proliferation, apoptosis, and cycle progression (16,18).…”

“…HSP90 is an important regulator of cell growth and survival, as well as being essential for the activity of a wide range of key oncogenic proteins, including kinases, transcription factors, and suppressor proteins (17,18). Many HSP90 client proteins are involved in processes such as proliferation, apoptosis, and cycle progression (16,18). Several reports have analyzed HSP90 expression in solid tumors and found that HSP90 expression is correlated with clinical prognosis, (5,16,19,20).…”

“…Preclinical studies and early clinical trials have confirmed the efficacy of HSP90 inhibition as a target therapy for many solid tumors (6,16,19,20). Recent data showed the therapeutic utility of HSP90 inhibitors in patients resistant to tyrosine kinase inhibitors (7,18). Little is known about the role of Topo I and HSP90 protein expression in KRAS-positive and negative CRCs, as well as the relationship between Topo I and HSP90 in CRC is not clear.…”