Inhibition of the heat shock protein 90 molecular chaperone <i>in vitro</i> and <i>in vivo</i> by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

Sharp, Swee Y.; Prodromou, Chrisostomos; Boxall, Kathy; Powers, Marissa; Holmes, Joanna L.; Box, Gary; Matthews, Thomas P.; Cheung, Kwai-Ming J.; Kalusa, Andrew; James, Karen; Hayes, Angela; Hardcastle, Anthea; Dymock, Brian; Brough, Paul A.; Barril, Xavier; Cansfield, Julie E.; Wright, Lisa; Surgenor, A.E.; Foloppe, Nicolas; Hubbard, Roderick E.; Aherne, Wynne; Pearl, Laurence H.; Jones, Keith; McDonald, Edward; Raynaud, Florence I.; Eccles, Sue; Drysdale, Martin J.; Workman, Paul

doi:10.1158/1535-7163.mct-07-0149

Cited by 139 publications

(114 citation statements)

References 54 publications

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confidence: 99%

“…(18,24) Several structurally distinct HSP90 inhibitors are progressing through clinical development with early indications of clinical responses in published phase I and II data. (25)(26)(27) While there are many similarities in the pharmacology of these different agents, (28,29) one prominent variable is the duration of the pharmacodynamic effect reported. (20,30,31) We have used fragment-based drug discovery to identify the high-affinity, long-acting HSP90 inhibitor, AT13387, which is currently being evaluated in clinical trials.…”

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confidence: 99%

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The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

Graham¹,

Curry²,

Smyth³

et al. 2012

Cancer Science

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A ubiquitously expressed chaperone, heat shock protein 90 (HSP90) is of considerable interest as an oncology target because tumor cells and oncogenic proteins are acutely dependent on its activity. AT13387 (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl] methanone, L-lactic acid salt) a novel, high-affinity HSP90 inhibitor, which is currently being clinically tested, has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. This inhibitor has induced the degradation of specific HSP90 client proteins for up to 7 days in tumor cell lines in vitro. The primary driver of cell growth (mutant epidermal growth factor receptors) was particularly sensitive to HSP90 inhibition. The long duration of client protein knockdown and suppression of phospho-signaling seen in vitro after treatment with AT13387 was also apparent in vivo, with client proteins and phospho-signaling suppressed for up to 72 h in xenograft tumors after treatment with a single dose of AT13387. Pharmacokinetic analyses indicated that while AT13387 was rapidly cleared from blood, its retention in tumor xenografts was markedly extended, and it was efficacious in a range of xenograft models. AT13387's long duration of action enabled, in particular, its efficacious once weekly administration in human lung carcinoma xenografts. The use of longer-acting HSP90 inhibitors, such as AT13387, on less frequent dosing regimens has the potential to maintain antitumor efficacy as well as minimize systemic exposure and unwanted effects on normal tissues. (Cancer Sci 2012; 103: 522-527) T he super-chaperone system is involved in the folding and maturation of newly synthesized proteins.(1,2) HSP90 in particular aids in the folding and maturation of a distinct subset of proteins, which includes kinases, cell surface receptors and transcription factors. (3,4) The N-terminal domain ATPase activity of HSP90 is essential for this function.(5) Inhibition of this domain induces remodeling of the HSP90 chaperone complex, resulting in the recruitment of ubiquitin ligases, polyubiquitination and subsequent proteasomal degradation of HSP90 client proteins.(6,7) Through this mechanism, the inhibition of a single target enzyme can have a wide effect on the stability and, hence, the function of a large set of client proteins. As many oncogenic proteins are HSP90 clients, HSP90 inhibition has been found to have broad antitumor effects.(8-10) In contrast to more recent targeted therapies, where the appearance of new driver mutations or resistance mutations result in a loss of efficacy, client protein mutation increases dependence on HSP90 chaperoning activity as these mutations tend to render the proteins less stable. (11)(12)(13) Previous studies have also demonstrated that the constitutively activated mutant forms of EGFR are particularly dependent on HSP90 both in vitro and in vivo, (14)(15)(16) indicating an HSP90 inhibitor may be particularly efficacious in mutant EGFR tumors.After HSP90 inhibiti...

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confidence: 99%

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confidence: 99%

The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

Graham¹,

Curry²,

Smyth³

et al. 2012

Cancer Science

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“…The cellular potency of these analogs is independent of NAD(P)H quinone oxidoreductase 1/DT-diaphorase and P-glycoprotein expression. 58 Hydroquinone ansamycins converted with quinone oxidoreductase 1 lead to a greater Hsp90 inhibitory activity and reduced toxicity.…”

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confidence: 99%

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

et al. 2011

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Heat-shock protein 90 (Hsp90) inhibitor downregulates c-Myc expression and upregulates the expression of tumor repressor proteins such as p53 and pRB, inhibiting the G1/S transition and causing G2/M arrest during cell cycle progression. The cycle progression is extensively controlled by the pRB/E2F signaling pathway. E2F is released from the pRB/E2F complex with the phosphorylation of pRB by cyclin-cyclin-dependent kinase (CDK) complexes. The released E2F promotes the transcription of target genes involved in cell cycle progression. The pRB/E2F signaling pathway is controlled by DNA methyltransferase-1 (Dnmt-1). The elevated expression of Dnmt-1 has been reported in carcinomas of the colon, lung and prostate. A defect of pRB expression in RbÀ/À cancer cells is caused by the aberrant methylation of CpG in the Rb promoter. The Hsp90 inhibitor disrupts the Dnmt-1/Hsp90 association and upregulates pRB expression. In this review, the Hsp90 inhibitors that show promise for cancer therapy are summarized.

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“…The 90 kDa heat shock protein (Hsp90) family plays an important role in the folding and activation of a range of client proteins involved in cell cycle regulation, steroid hormone responsiveness and signal transduction (Stebbins et al 1997;Roe et al 1999;Piper 2001;Maloney & Workman 2002;Jez et al 2003;Neckers 2003;Wright et al 2004;Chiosis et al 2006;Sharp 2007;Eccles et al 2008;Taldone et al 2008). Hsp90 is a molecular chaperone whose association is required for the stability and function of multiple mutated, chimeric and over-expressed signalling proteins that promote cancer cell growth and/or survival.…”

Section: Introductionmentioning

confidence: 99%

“…As such they have shown promising levels of anti-tumour activity in preclinical model systems, and one Hsp90 inhibitor, 17-AAG, is currently in Phase II clinical trials (Sharp 2007). In addition, several synthetic Hsp90 inhibitors are currently in Phase I evaluation, including a purine-scaffold agent CNF-2024 (Chiosis et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Dynamics of conserved waters in human Hsp90: implications for drug design

Yan

Grant

Richards

2008

J. R. Soc. Interface.

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The flexibility of a promising protein target, human heat shock protein 90 (Hsp90), is investigated by molecular dynamics simulations. These simulations focus on: (i) the interactions between the protein and conserved water molecules; and (ii) the interactions of the ligand PU3, the conserved water molecules and the protein. This is followed by a virtual screening docking study of the PU3 family of compounds and Hsp90 incorporating several conserved water molecules.

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Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

Cited by 139 publications

References 54 publications

The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

Dynamics of conserved waters in human Hsp90: implications for drug design

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