Abstract 1540
The PIM serine/threonine kinase family is composed of three highly homologous members; PIM1, PIM2 and PIM3, identified by the ability of the prototype member PIM1 to drive ...lymphomagenesis in mice. Upregulation of PIM1 and PIM2 is observed in leukemias and lymphomas, including AML, NHL and CLL, highlighting the potential of these kinases as therapeutic targets in these indications. PIMs are downstream effectors of many cytokine and growth factor signaling pathways and are direct transcriptional targets of STAT transcription factors activated by these pathways. PIMs can phosphorylate multiple substrates to mediate cell proliferation and survival. Here we describe the function of AZD1208, an orally available, potent and highly selective PIM inhibitor that effectively inhibits all three isoforms. AZD1208 inhibits the growth of several AML cell lines and sensitivity correlates with the level of PIM1 expression, STAT5 activation and presence of protein tyrosine kinase mutation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells in culture. This is accompanied by a dose-dependent reduction in pBAD serine 112 and other substrates, as well as an increase in cleaved caspase 3. AZD1208 suppresses the growth of MOLM-16 and KG-1a xenograft tumors in vivo in a dose proportional manner. In addition, AZD1208 leads to potent inhibition of colony growth of primary AML cells from bone marrow aspirates and downregulates phosphorylation of PIM targets. These results underscore the therapeutic potential of PIM kinase inhibition by AZD1208 for the treatment of AML.
Keeton:AstraZeneca: Employment, Equity Ownership. Palakurthi:AstraZeneca: Employment, Equity Ownership. Alimzhanov:AstraZeneca: Employment, Equity Ownership. Grondine:AstraZeneca: Employment, Equity Ownership. Chen:AstraZeneca: Employment, Equity Ownership. Brown:AstraZeneca: Employment, Equity Ownership. McEachern:AstraZeneca: Employment, Equity Ownership. Cao:AstraZeneca: Employment, Equity Ownership. Chinnappan:AstraZeneca: Employment, Equity Ownership. Shen:AstraZeneca: Employment, Equity Ownership. Dakin:AstraZeneca: Employment, Equity Ownership. Zheng:AstraZeneca: Employment, Equity Ownership. Lamb:AstraZeneca: Employment, Equity Ownership. Wu:AstraZeneca: Employment, Equity Ownership. Chen:AstraZenenca: Employment, Equity Ownership. Lyne:AstraZeneca: Employment, Equity Ownership. Huszar:AstraZeneca: Employment, Equity Ownership.
B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a ...novel class of small molecules that inhibit mutant B-RafV600E kinase activity both in vitro and in vivo. Investigations into the structure–activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-RafV600E in vitro and showed preferential antiproliferative activity in mutant B-RafV600E cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-RafV600E A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in nonmutant B-Raf cell lines in vitro.
Regulation of translation initiation plays a critical role in the control of cell growth and division in eukaryotic cells. Translation of many growth regulatory proteins including cyclins depends ...critically on translation initiation factors because their mRNAs are translated inefficiently. We report that clotrimazole, a potent antiproliferative agent both
in vitro
and
in vivo
, inhibits cell growth by interfering with translation initiation. In particular, clotrimazole causes a sustained depletion of intracellular Ca
2+
stores, which results in activation of PKR, phosphorylation of eIF2α, and thereby in inhibition of protein synthesis at the level of translation initiation. Consequently, clotrimazole preferentially decreases the expression of the growth promoting proteins cyclin A, E and D1, resulting in inhibition of cyclin-dependent kinase activity and blockage of cell cycle in G
1
.
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