Posaconazole, a Second-Generation Triazole Antifungal Drug, Inhibits the Hedgehog Signaling Pathway and Progression of Basal Cell Carcinoma

Abstract

Deregulation of Hedgehog (Hh) pathway signaling has been associated with the pathogenesis of various malignancies, including basal cell carcinomas (BCC). Inhibitors of the Hh pathway currently available or under clinical investigation all bind and antagonize Smoothened (SMO), inducing a marked but transient clinical response. Tumor regrowth and therapy failure were attributed to mutations in the binding site of these small molecule SMO antagonists. The anti-fungal itraconazole was demonstrated to be a potent SMO antagonist with a distinct mechanism of action from that of current SMO inhibitors. However, itraconazole represents a suboptimal therapeutic option due to its numerous drug-drug interactions. Here we show that posaconazole, a second generation triazole anti-fungal with minimal drug-drug interactions and a favorable side effect profile, is also a potent inhibitor of the Hh pathway that functions at the level of SMO. We demonstrate that posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo. Our results suggest that posaconazole, alone or in combination with other Hh pathway antagonists, may be readily tested in clinical studies for the treatment of Hh-dependent cancers.

C1GALT1 predicts poor prognosis and is a potential therapeutic target in head and neck cancer

“…2c ). Aside from itraconazole, ketoconazole and posaconazole were reported to exhibit anti-cancer activities [ 23 , 24 ]. Therefore, we examined the effect of other triazole derivatives, including terconazole, ketoconazole, and posaconazole, on Tn expression.…”

树鼩(Tupaia belangeri chinensis)基底细胞癌模型的建立

“…In addition, a recent study indicated that the MK-4101 molecule can attenuate the Hh signaling pathway through inhibition of Gli, alteration of IGF, and Wnt signaling pathway activities, thus proving to be a promising therapeutic drug for BCC patients ( Filocamo et al, 2016 ). A second-generation antifungal drug posaconazole, which showed distinct mechanisms from cyclopamine or cyclopamine competitive inhibitors, exhibits better drug-drug interaction and fewer side effects than current SMO inhibitors, and could provide a novel strategy for clinical drug combinational therapy ( Chen et al, 2016 ).…”

Development of posaconazole-based analogues as hedgehog signaling pathway inhibitors

“…Because 18 was significantly less active than 17 against the Hh signaling pathway (Table 2 below), we did not optimize the conditions necessary to reduce 18 to the corresponding alcohol. A similar synthetic route was also utilized to synthesize an ITZ analogue incorporating the propanoic acid side chain (21) to explore whether incorporation of this moiety affected the activity of the des-triazole ITZ scaffold (Scheme 3).…”

“…[12][13][14][15][16] Posaconazole (PSZ) and itraconazole (ITZ) are clinically approved azole antifungals that have been identified as Hh pathway inhibitors in vitro and in vivo [17][18][19][20]. Previous studies strongly suggest that both of these drugs inhibit the Hh pathway by directly binding Smo [17][18][21][22]. PSZ and ITZ retain their anti-Hh activity in the presence of mutant forms of Smo that confer resistance to vismodegib and sonidegib, highlighting their potential as improved anti-cancer drugs targeting the Hh pathway.…”