Glasdegib (PF-04449913) inhibits sonic hedgehog (Shh) stimulated luciferase expression in mouse embryonic fibroblasts with an IC50 of 6.8 nM. In vitro microsomal assays, PF-04449913 have high clearance in rat and low clearance in dog and human, without inhibiting any of the major cytochrome P450 isoforms.
In vivo, CD34+ cord blood engrafted NSG mice are treated with Glasdegib (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.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 65 mg/mL|
GLI2 inhibition abrogates human leukemia stem cell dormancy.
Sadarangani A, et al. J Transl Med. 2015 Mar 21;13:98. PMID: 25889765.
Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened.
Munchhof MJ, et al. ACS Med Chem Lett. 2011 Dec 21;3(2):106-11. PMID: 24900436.
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