New small-molecule inhibitors of the Hedgehog signaling pathway

In a growing embryo, cells develop differently in the head or tail end of the embryo, the left or right, and other positions. They also form segments which develop into different body parts. The Hedgehog signaling pathway (Hh) gives cells information that they need to make the embryo develop properly. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. When the pathway malfunctions, it can result in diseases like basal cell carcinoma.

Fig.1. Components of the Hh signaling pathway and molecular sites targeted by Hh pathway inhibitors.

Inhibitors of the Hedgehog molecular signaling pathway have emerged in recent years as a promising new class of potential therapeutics for cancer treatment. Numerous drug discovery efforts have resulted in the identification of a wide variety of small molecules that target different members of this pathway, including Smoothened (Smo), Sonic hedgehog protein (Shh), and Gli1. Several Smo inhibitors have now entered human clinical trials, and successful proof-of-concept studies have been carried out in patients with defined genetic mutations in the Hh pathway.

The Smoothened receptor has distinguished itself as the most “druggable” target in the pathway to date, as demonstrated by the structurally diverse array of both naturally occurring and fully synthetic small-molecule Smo inhibitors reported, and the recent successful results from first-in-human, proof-of-concept studies with several of these inhibitors will undoubtedly spur more interest in this area. Meanwhile, efforts are ongoing to identify additional druggable nodes in the pathway, and promising initial results have been demonstrated for targeting the Sonic hedgehog protein (Shh) and the downstream target Gli1 with small-molecule inhibitors.

 

OTAVAchemicals offers you two recently synthesized compounds with potent Smo receptor inhibiting activity originally prepared on the basis of the structure of the acylthiourea Smo antagonist (MRT-10) by ligand-based structural optimization (see Ref. 1).

 

7070707158	7070707159

 

• Compounds are for prompt delivery (by FedEx)
• Delivery time is 5-9 business days
• Quality control by NMR and/or GC/LC/MS
• Purity: 90%+
• NMR spectra are available upon request
• Available amounts: milligram and gram quantities
• Supplied as dry powders
• Re-synthesis is possible

 

Please contact us to order these compounds

 

References:

1. Solinas A, Faure H, Roudaut H, Traiffort E, Schoenfelder A, Mann A, Manetti F, Taddei M, Ruat M. Acylthiourea, acylurea, and acylguanidine derivatives with potent hedgehog inhibiting activity. J Med Chem. 2012 Feb 23;55(4):1559-71.
2. Peukert S, Miller-Moslin K. Small-molecule inhibitors of the hedgehog signaling pathway as cancer therapeutics. ChemMedChem. 2010 Apr 6;5(4):500-12.