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TOR GW9508 inhibitor GDC 0941 138 . The combination of GNE 652 and GDC 0941 resulted in stronger inhibition on the phosphorylation of PRAS40, p70S6K, S6RP and 4EBP1 in several myeloma cell lines 139 . 4 ARR0459339 Array Biopharma Inc. ARR09459339 is actually a triazolopyridine that inhibits PIM1, 2 and 3 IC50 values: 0.8, 5 and 36, respectively and only moreover inhibited Haspin in a 256 kinase panel. AR00459339 was identified to be preferentially cytotoxic to FLT3 ITD cells. Unlike FLT3 inhibitors, AR00459339 did not suppress the phosphorylation of FLT3 but did promote the dephosphorylation on the downstream FLT3 targets STAT5, AKT, and Negative. Combining AR00459339 with a FLT3 inhibitor 100:1 resulted in additive to mildly synergistic cytotoxic effects.
AR00459339 was cytotoxic to FLT3 ITD samples from patients with secondary resistance to FLT3 inhibitors, suggesting a GW9508 novel benefit from combining these agents 140 . 4 A95386 Cpd 14j Abbot Laboratories A95386 is actually a 3H benzo 4,5 thieno 3,2 d pyrimidin 4 one and a pan PIM inhibitor at low nanomolar concentrations IC50 values for PIm1, 2 and 3: 0.5 nM, 2 nM and 3 nM, respectively that shows selectivity against a panel of 15 kinases 141 . Cpd 14j inhibited the growth of K562 cells, presenting an IC50 value of 1.7 mM, and efficiently interrupted the phosphorylation of Negative in both K562 and LNCaP cell lines. The pharmacokinetics of Cpd 14j indicated a bioavailability of 76 soon after oral dosing in CD 1 mice 141 . In a cell line derived from Em Lenalidomide myc mice, inhibition of PIM kinases with Cpd 14j led to inhibition of Negative phosphorylation and induction of cell death associated with downregulating Myc transcriptional target genes.
4.0. K00486 University School of Medicine, Loma Linda, California and Plexxikon, Inc. This compound is an imidazopyridazine that preferentially inhibits PIM1 vs. PIM2 IC50 values: 40 and 2500 nM, respectively 106 . Ba F3 overexpressing PIM1 cells grown within the absence of IL 3 and treated with K00485 showed a dose dependent reduce in survival RNA polymerase soon after 24 h. Treatment of Jurkat cells with K00486 resulted in decreases in CXCL12 and PMA induced phosphorylation of CXCR4 at S339, revealing that PIM1 acts as a regulator of CXCL12 CXCR4 mediated homing and migration 142 Triazolo benzo c 2 6 napthyridines Cylene Pharmaceuticals These compounds had been discovered by relocating and modifying functional groups on the potent CK2 inhibitor CX 4945 silmitasertib .
These molecules exerted a powerful in vitro antiproliferative effect in solid and hematological cancer cell lines Pc 3, MDAMB231, MiPaca 2, MV4:11 and K562 . Within the most sensitive leukemia cell line MV4:11 , essentially the most potent compound showed an IC50 of 30 nM associated Lenalidomide towards the inhibition of Negative phosphorylation at S112. Despite the fact that CX 4945 is described as a potent CK2 inhibitor IC50 value: 1 nM , in biochemical assays, this compound showed IC50 values of 48 nM and 186 nM for PIM1 and PIM2, respectively. Consequently, the possibility can't be ruled out that its in vivo growth inhibition effect is because of a combination of CK2 and PIM inhibition 143,144 CX 6258 Cylene Pharmaceuticals This compound a 3 5 2 oxoindolin 3 ylidene methyl furan 2 yl amide derivative that acts as a pan PIM inhibitor IC50 values for PIM1, 2 and 3: 15, 25 and 16 nM, respectively .
It also inhibits FLT3 at a concentration of 134 nM and was identified to be selective in a panel of 107 kinases. The antiproliferative activity of CX 6258 was examined in a panel of cell lines derived from human solid tumors and hematological malignancies, showing robust antiproliferative activity against all of the cell lines tested. Cell lines derived from acute GW9508 leukemias had been essentially the most sensitive. Treatment on the MV4:11 cell line with CX 6258 led to downregulation of Negative and 4E BP1 phosphorylation, but not of FLT3 autophosphorylation. In Pc 3 cells, the combination of CX 6258 with doxorubicin 10:1 molar ratio and placitaxel 100:1 molar ratio showed synergistic antiproliferative effects.
In vivo, every day oral therapy of MV4:11 and Pc 3 tumor xenografts resulted Lenalidomide in inhibition of tumor growth in a dose dependent manner 145 ETP 45299, ETP 39010 and 1,2,3 triazolo 4,5 b pyridine derivatives Spanish National Cancer Analysis Center ETP 45299 represents chemical optimization GW9508 on the imidazo 1,2 b pyridazine scaffold. It is a potent and selective inhibitor of PIM1 and, to a lesser extent, of PIM3. ETP 45299 exhibits a Ki of 30 nM for PIM1 and Ki values of 1049 and 81 nM for PIM2 and PIM3, respectively. The compound showed no considerable inhibitory activity against an additional 22 unrelated kinases. ETP 45299 inhibited the phosphorylation Lenalidomide of Negative and 4EBP1 in a dosedependent manner and induced cell cycle arrest in MV4:11 tumor cells. ETP 45299 suppressed the proliferation of various non solid and solid human tumor cell lines. It also suppressed the migration of MDA MB231 breast cancer cells through Matrigel, corroborating the possible usefulness of PIM inhibitors in treating metastatic disease. Dual inhibi