Editorial :

Abstract

In the last decade, the molecular chaperone HSP90 has emerged as an important target in cancer therapeutics and has subsequently become the focus of several drug discovery and development efforts. The first-in-class HSP90 inhibitor 17-AAG entered into Phase I clinical trial in 1999. Today 13 HSP90 inhibitors representing multiple drug classes, with different modes of action, are undergoing clinical evaluation. The present review will highlight the involvement of HSP90 in regulating and maintaining the transformed phenotype, provide an overview on current HSP90 inhibitors and further update on the most relevant patents which have recently appeared in the literature.

Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells

“…We finally investigated whether resistance to PU-H71 could be overcome by treatment with two alternative, structurally distinct ATP-competitive HSP90 inhibitors that are currently in clinical development, the geldanamycin derivative tanespimycin (also known as 17-AAG) and the second-generation triazole ganetespib (also known as STA9090) [4, 30]. To this end, parental and PU-H71-resistant cell lines were incubated with 5 μM tanespimycin, 100 nM ganetespib and 1 μM PU-H71, and viable cells were counted after three days.…”

“…The capacity of HSP90 to protect key oncogenic proteins from degradation has spurred the development of small molecules that interfere with the conformational cycling of HSP90 through binding to its N-terminal nucleotide pocket and locking it in a nucleotide-bound form [4], which in turn leads to the depletion of misfolded, inactive or unstable client proteins. There are, or have been, nearly 20 HSP90 inhibitors in clinical development [5], which are structurally classified as derivatives of geldanamycin, resorcinol, purine, dihydroindazolone, dihydropyridopyrimidine and tropane [6].…”

Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer

“…In the past years there has been a considerable increase in the discovery of HSP90 inhibitors, progressing from first-generation derivatives of natural products to second and third-generation fully synthetic small molecules with improved pharmacokinetic profiles [13]. …”

“…However, it was never evaluated in clinical trials mainly due to metabolic instability, limited solubility, and induction of severe hepatotoxicity in animals [12]. 17-AAG (Tanespimycin), an analog molecule chemically derived from GA, was the first HSP90 inhibitor to enter clinical trials [13]. In preclinicals models it has shown antitumor activity in various types of cancer, such as colon, breast, ovarian, and melanoma tumors [12, 14].…”

FS-93, an Hsp90 inhibitor, induces G2/M arrest and apoptosis via the degradation of client proteins in oncogene addicted and derived resistant cancer cells

“…Upon inhibition of Hsp90, multiple oncogenic signaling cascades can be attenuated effectively, which makes Hsp90 a promising target for cancer therapy [13, 14]. Tremendous preclinical evidence has proved the rationale for targeting Hsp90 and dozens of Hsp90 inhibitors, including 17-DMAG, IPI-504, NVP-AUY922, BIIB021 and STA-9090, have been discovered accordingly and are currently in phase I-III clinical trials across multiple tumor types [15-17]. …”