Glasdegib (PF-04449913) is a potent, and orally bioavailable Smoothened (Smo) inhibitor with IC50 of 5 nM. Phase 2.

98%

Store at -20℃ for one year（Powder）；Store at 2-4℃ for two weeks；Store at -20℃ for six months after dissolution.

DMSO:47 mg/mL (125.52 mM)

Smo

PF-04449913 inhibits sonic hedgehog (Shh) stimulated luciferase expression in mouse embryonic fibroblasts with an IC50 of 6.8 nM; and significantly reduces medulloblastoma growth in a Ptch1+/-p53+/- allograft model at doses that decreased murine Shh target gene expression. In stromal co-culture experiments, FACS analysis demonstrates a significant reduction in BC LSC by PF-04449913 when compared with normal progenitors. Importantly, human BC LSC engrafted RAG2-/-γC-/- mice treated daily with PF-04449913 compared with vehicle treated controls have a significant spleen weight reduction (p=0.006). This reduction in leukemic burden corresponded with decreased GLI2 protein expression, as determined by both nanoproteomic analysis of FACS purified human progenitors and GLI2 confocal fluorescence microscopic analysis of splenic sections.

Human BC LSC engrafted RAG2-/-γC-/- mice treated daily with PF-04449913 compared with vehicle treated controls had a significant spleen weight reduction (p=0.006). When CD34+ cord blood engrafted NSG mice are treated with PF-04449913, the frequency of human CD45+ cells, progenitors and both myeloid and lymphoid cell fate commitment remained comparable to vehicle treated controls indicating that unlike LSC, normal human HSC cell fate decisions are Hh pathway independent. These results highlight the important niche dependent effects of selective SMO inhibition that induce GLI2 downregulation in a cell type and context specific manner.