Abstract
Inhibition of aberrant Hedgehog (Hh) pathway had been proved to be a promising therapeutic intervention in cancers like basal cell carcinoma (BCC), medulloblastoma (MB), and so on. Two drugs (Vismodegib, Sonidegib) were approved to treat BCC and more inhibitors are in clinical investigation. However, the adverse effects and drug resistance restricted the use of Hh inhibitors. In the present study, 61 synthesized compounds containing central backbone of phthalazine or dimethylpyridazine were screened as candidates of new Hh signaling inhibitors by performing dual luciferase reporter assay. Among the compounds, L-4 exhibited an IC50 value of 2.33 nM in the Shh-Light II assay. L-4 strongly inhibited the Hh pathway in vitro and blocked the Hh pathway by antagonizing the smoothened receptor (Smo). Remarkably, L-4 could significantly suppress the Hh pathway activity provoked by Smo mutant (D473H) which showed strong resistant properties to existing drugs such as Vismodegib. Orally administered L-4 exhibited prominent dose-dependent anti-tumor efficacy in vivo in Ptch+/-; p53-/- MB allograft model. Furthermore, L-4 showed good tolerance in acute toxicity test using ICR mice. These evidences indicated that L-4 was a potent, well-tolerated, orally active inhibitor of Hedgehog pathway, and might be a promising candidate in development of Hh-targeted anti-cancer drugs.
Highlights
The Hedgehog pathway is evolutionarily conserved and plays vital roles in the early development of the mammals by controlling cell proliferation and differentiation (Pomeroy et al, 2002; Jiang and Hui, 2008)
Desert hedgehog) which can stimulate the Hh pathway, PTCH which represses the activity of smoothened receptor (Smo), Smo which acts as a positive regulatory protein, and the glioma associated oncogene (GLI) family (Ruiz and Altaba, 1997)
The results indicated that the inhibition of Smo by L-4 had a negative effect on translocation of Gli1, and inhibited the Gli1 expression
Summary
The Hedgehog pathway is evolutionarily conserved and plays vital roles in the early development of the mammals by controlling cell proliferation and differentiation (Pomeroy et al, 2002; Jiang and Hui, 2008). Aberrant activation of Hh pathway signaling leads to abnormal development of the tissues and is linked to many malignant tumors like BCC, MB, and so on (Epstein, 2008; Rimkus et al, 2016; Tan et al, 2018). Mutant PTCH1 was reported to cause the human developmental disorder Gorlin syndrome which increased a notable risk of advanced BCC and MB This indicated that Hh pathway contributed to the formation of MB (Hahn et al, 1996). Cyclopamine is the first Hh inhibitor to be found which advances our research of the Hh pathway as a therapeutic target substantially (Incardona et al, 1998; Tremblay et al, 2009). Evaluation of anti-tumor effects of L-4 in vitro and in vivo was conducted
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