The Hedgehog (Hh) protein family includes Sonic (Shh), Indian (Ihh), and Desert (Dhh) hedgehogs, which regulates numerous events in embryonic development. Patched-1 is a receptor for all of the hedgehog proteins. Ptch-1 inhibits Smoothened (Smo) when Hh is in absence. In contrast, When Hh binds to Ptch-1, Smo will initiate a signaling cascade that results in activation of a transcription factor, Gli-1.
Aberrant activation of the Hh pathway is associated with basal cell carcinoma (BCC) and medulloblastoma. BCC is the most common cancer in the western world. Moreover, mutations of PTCH1 and SMO can activate the pathway in the absence of Hh have been found in >70% of sporadic BCCs. And regardless of where the particular oncogenic mutations exist. BCC samples have elevated levels of a more downstream component of the pathway, the transcription factor Gli-1.
The link between human BCC and Hh signaling has been researched in animal studies. Furthermore, many researchers suggest that compounds that can suppress aberrantly-activated Hh signaling may cause the growth arrest of BCC cells and can provide an effective chemotherapeutic for BCC.
In this article, we will introduce a novel, cell-permeable Hedgehog signaling pathway inhibitor, CUR61414.
CUR61414 is a small-molecule member of the aminoproline class of compounds and selectively binds to smoothened (Smo) with a Ki value of 44 nM.
Firstly, in Ptch-Null Cells carrying inactive Ptch-1. CUR61414 acts downstream of Ptch-1, strongly inhibits Hh signaling in these cells.
Nextly, in Vitro BCC Model System, CUR61414 can arrest the proliferation of basal cells within the BCC-like lesions. At the same time, it induces cells to undergo apoptosis resulting in complete regression of the lesions, without affecting neighboring skin cells.
In vivo. In Ptch+/−-LacZ heterozygous mice exposed to UV light irradiation for 6-9 months. CUR61414 induces a significant increase in apoptotic nuclei can be seen in basaloid nests after CUR61414 treatment and no overt toxicity is observed in the skin surrounding the lesions.
In summary, CUR61414 is a synthetic inhibitor that specifically binds to and antagonizes the activity of Smo in the Hh signaling pathway. Moreover, CUR61414 is a desirable candidate for drug development due to its good physicochemical properties.
Reference
Williams JA, et al. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4616-21. Epub 2003 Apr 4.