General, Cpd 9a showed excellent microsomal stability and minimal inhibition of human cytochrome P450s. The pharmacokinetic parameters estimated for Cpd 9a immediately after intravenous administration 5 mg kg in BALB C mice, which includes its plasmatic half life 0.95 h and plasmatic clearance eight L h kg , indicated that optimization of this compound was necessary. Examination of mechanism of action of this compound in Jeko one human mantle lymphoma xenografts in SCID mice showed a 40 reduction of Negative phosphorylation at S112 when compared to a manage group receiving vehicle 149 Quercetagetin Plexxikon The flavonol quercetagetin three,30,40,5,six,seven hydroxyflavone may be a very selective PIM1 inhibitor IC50 worth: 340 nM . Quercetagetin was ready to inhibit the phosphorylation of Awful in a dosedependent manner in RWPE2 prostate cancer cells overexpressing PIM1, inducing growth inhibition at concentrations that blocked PIM1 kinase exercise. On top of that, the ability of quercetagetin to inhibit the growth of other prostate epithelial cell lines depended around the degree of PIM1 protein present 150 .
In molecule library vascular smooth muscle cells, PDGFbb induced PIM1 mRNA expression, followed by protein upregulation and an increase in proliferation. This result was successfully blocked by either quercetagetin treatment method or adenoviral introduction of PIM1 shRNA 151 2 Azaindole derivatives University of Tokyo Derivatives of two azaindole are potent PIM1 and PIM3 and FLT3 inhibitors by using a lower nanomolar IC50 and weren’t located to display action against 50 other kinases tested. These compounds potently inhibited the growth of MV4:eleven cells GI50 43 nM , exhibiting only a negligible impact to the development of the regular human diploid lung fibroblast cell line WI 38. Additionally, one particular derivative, Cpd 14, inhibited Undesirable phosphorylation and induced G1 arrest within a dose dependent method. Cpd 14 is metabolically steady, will not inhibit leading cytochrome P450s at a concentration of 10 mM and exhibits reasonable inhibition on the potassium channel hERG subunit 152 CXR1002 CXR Discovery CXR1002 is an ammonium salt of perfluorooctanoic acid.
This is a lipid mimetic that causes endoplasmic reticulum stress and inhibits PIM kinases IC50 values for PIM1, two and 3: forty, 170, 240 Aprepitant mM, respectively . CXR1002 inhibited the phosphorylation of Mdm2 by PIM1 in vitro and quickly alters the level of PIM1 when utilized to K562 cells. Hematological cell lines demonstrated the highest sensitivity to CXR1002, but this compound can also be lively in Computer three, HT29, HepG2, Panc one and A549 xenograft models. CXR1002 showed sturdy synergism in combination with gemcitabine and doxorubicin in pancreatic, ovarian and hepatic carcinoma cell lines 153 Clinical trials In November 2008, the FDA granted SuperGen permission to begin a phase I clinical trial to check the safety, tolerability and pharmacokinetics of SGI 1776 in patients with sound tumors, notably those with castration resistant prostate cancer and refractory non Hodgkin lymphoma.