Modulators of the hedgehog signaling pathway

Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened

“…1 The Hh signaling cascade is activated by binding of one of three Hh ligands, Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), or Desert Hedgehog (Dhh), to their receptor Patched (Ptch). 2 This leads to the activation of Smo, a 7-transmembrane protein, by relieving Ptch's suppressive effect on Smo, triggering a cascade that results in the activation of three transcription factors, Gli1, Gli2, and Gli3, leading to proliferation.…”

“…Deregulation of the pathway via mutations or autocrine or paracrine mechanisms of ligand overexpression leads to hyperproliferative conditions. 1 Over a decade ago, Beachy reported the first Smo antagonist, cyclopamine ( Figure 1). 3 Cyclopamine was isolated from the corn lilly, Veratrum californicum, by Richard Keeler and coworkers in 1964.…”

“…Deprotection and acylation with 3-dihydrobenzo-[b] [1,4]dioxine-6-carbonyl chloride completed the synthesis of 8. The remaining diastereomers were prepared in an analogous manner.…”

“…Commercially available (2R,4S)-1-tert-butyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate (9) was converted to the mesylate that was displaced with sodium azide. Reduction of the azide and acylation with 3-dihydrobenzo-[b] [1,4]dioxine-6-carbonyl chloride (7) afforded 11. Hydrolysis of the ester, activation, and coupling with 1,2-diaminobenzene gave 14, which was treated with acetic acid, forming the benzimidazole ring.…”

Reprogramming to Pluripotency Using Small Molecule Compounds

“…Although small molecule inhibitors exist for these targets, further investigation is required to determine their inhibitory effect on iPSC production. Potent small molecule modulators of the SHH pathway have been recently reviewed (Heretsch, Tzagkaroulaki et al 2010).…”