4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer

Abstract

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

“…NVP-AUY922 (compound 38, Figure 5) is one of the most potent synthetic small molecular mass hsp90 inhibitor yet described (Ki ¼ 9.0 and 8.2 nM for Hsp90a and b, respectively; Brough et al, 2008;Eccles et al, 2008;Stu¨hmer et al, 2008). This isoxazole derivative inhibits the proliferation of human tumor cell lines with IC 50 values of 2.3-50 nM, and induces marked accumulation in either G 1 or G 1 plus G 2 -M phases in most cell lines (Eccles et al, 2008).…”

Novel HSP90 inhibitors, NVP-AUY922 and NVP-BEP800, radiosensitise tumour cells through cell-cycle impairment, increased DNA damage and repair protraction

“…Thus, the inhibitor of Hsp90, geldanamycin, and its derivatives significantly enhance the radiosensitivity of tumour cell lines derived from a variety of histologies, including glioma, prostate, pancreas and cervix (Bisht et al, 2003;Enmon et al, 2003;Machida et al, 2003;Russell et al, 2003;Bull et al, 2004;Harashima et al, 2005;Dote et al, 2006). However, geldanamycins have several limitations, including poor solubility, formulation difficulties, hepatotoxicity and extensive metabolism by polymorphic enzymes, along with drug efflux by P-glycoprotein (Kelland et al, 1999;Eiseman et al, 2005;Brough et al, 2008;Eccles et al, 2008). Therefore, there has been considerable effort to design small synthetic inhibitors of Hsp90 with improved bioavailability and lower toxicity.…”

Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

“…The challenge for development of an effective Ph-positive leukemia therapy is therefore to develop an alternative treatment strategy that does not rely solely on kinase domain inhibition but rather results in degradation of the offending BCR-ABL protein regardless of its mutation status. AUY922 is a most potent resorcinylic isoxazole amide HSP90 inhibitor, which binds to the adenosine triphosphate-binding pocket of HSP90 (Brough et al, 2008). AUY922 has excellent cellular potency against a panel of tumor cell lines (Brough et al, 2008;Eccles et al, 2008;Stuhmer et al, 2008).…”

“…AUY922 is a most potent resorcinylic isoxazole amide HSP90 inhibitor, which binds to the adenosine triphosphate-binding pocket of HSP90 (Brough et al, 2008). AUY922 has excellent cellular potency against a panel of tumor cell lines (Brough et al, 2008;Eccles et al, 2008;Stuhmer et al, 2008). In addition, optimization of pharmacokinetic properties led to robust therapeutic responses in a wide variety of human tumor xenografts tightly linked to high intratumor concentrations of compound and phamacodynamic response (Eccles et al, 2008).…”

“…NVP-AUY922 is a novel 4,5-diaryloxazole adenosine triphosphate-binding site heat shock protein 90 (HSP90) inhibitor, which has been shown to inhibit the chaperone function of HSP90 and deplete the levels of HSP90 client protein (for example, ErbB2, Akt, Raf and BcrAbl) (Brough et al, 2008;Eccles et al, 2008;Stuhmer et al, 2008). Combining AUY922 with ABL kinase inhibitors may provide several advantages, such as enhanced efficacy and reducing the potential emergence of new resistant mutations.…”