Although molecularly targeted therapy with imatinib has improved treatments of chronic myeloid leukemia (CML), clinical resistance gradually develops in patients with accelerated or blast phase CML. The inability of imatinib to cure CML suggests that inactivation of BCR-ABL kinase activity alone is not sufficient to control the disease. Aberrant STAT signaling and constitutive STAT5 or STAT3 activation are frequently found in both acute and chronic leukemia. Constitutive activation of STAT5 and STAT3 are associated with imatinib resistance on leukemia cells. Development of drugs targeting SH2 domains of STAT5 and STAT3 provides a novel strategy for the treatment of the imatinib-resistant CML. Here, molecular docking and molecular dynamics simulations were used to investigate the interactions of the drugs targeting STAT3 and STAT5 receptors at molecular level. The calculated binding free energies are consistent with the ranking of the experimental affinities and our simulations also explained their differences in binding energy. Then virtual screening based on molecular docking and molecular dynamics was applied to screen a set of ~1500 compounds for dual inhibitors of the SH2 domains of STAT5 and STAT3. Three top score compounds obtained in virtual screening were compound 660, 304, and 561. Results show that the three predicted dual-inhibitors are well fitted within the two binding domains and are predicted to present improved STAT5 and STAT3 SH2 inhibitory activity.

01 Jun 1997·Journal of Biological ChemistryQ2 · BIOLOGY

Two Discrete Regions of Interleukin-2 (IL2) Receptor β Independently Mediate IL2 Activation of a PD98059/Rapamycin/Wortmannin-insensitive Stat5a/b Serine Kinase

Q2 · BIOLOGY

Article

Author: Hallgeir Rui ; Lothar Hennighausen ; Luis DaSilva ; M. Grazia Malabarba ; Robert A. Kirken ; Jun Xu ; William L. Farrar ; Rebecca A. Erwin ; Xiuwen Liu

Many cytokines, hormones, and growth factors activate Janus kinases to tyrosine phosphorylate select members of the Stat transcription factors. For full transcriptional activation, Stat1 and Stat3 also require phosphorylation of a conserved serine residue within a mitogen-activated protein kinase phosphorylation consensus site. On the other hand, two recently identified and highly homologous Stat5a and Stat5b proteins lack this putative mitogen-activated protein kinase phosphorylation site. The present study set out to establish whether Stat5a and Stat5b are under the control of an interleukin-2 (IL2)-activated Stat5 serine kinase. We now report that IL2 stimulated marked phosphorylation of serine and tyrosine residues of both Stat5a and Stat5b in human T lymphocytes and in several IL2-responsive lymphocytic cell lines. No Stat5a/b phosphothreonine was detected. Phosphoamino acid analysis also revealed that Stat5a/b phosphotyrosine levels were maximized within 1-5 min of IL2 stimulation, whereas serine phosphorylation kinetics were slower. Interestingly, IL2-induced serine phosphorylation of Stat5a differed quantitatively and temporally from that of Stat5b with Stat5a serine phosphorylation leveling off after 10 min and the more pronounced Stat5b response continuing to rise for at least 60 min of IL2 stimulation. Furthermore, we identified two discrete domains of IL2 receptor beta (IL2Rbeta) that could independently restore the ability of a truncated IL2Rbeta mutant to mediate Stat5a/b phosphorylation and DNA binding to the gamma-activated site of the beta-casein gene promoter. These observations demonstrated that there is no strict requirement for one particular IL2Rbeta region for Stat5 phosphorylation. Finally, we established that the IL2-activated Stat5a/b serine kinase is insensitive to several selective inhibitors of known IL2-stimulated kinases including MEK1/MEK2 (PD98059), mTOR (rapamycin), and phosphatidylinositol 3-kinase (wortmannin) as determined by phosphoamino acid and DNA binding analysis, thus suggesting that a yet-to-be-identified serine kinase mediates Stat5a/b activation.

CancersQ2 · MEDICINE

Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies

Q2 · MEDICINE

ArticleOA

Author: Ramazanov, Ilfir R. ; Dzhemileva, Lilya U. ; Makarov, Alexey A. ; Makarova, Elina Kh. ; D’yakonov, Vladimir A. ; Dzhemilev, Usein M.

The first Z-stereoselective method was developed for the synthesis of unsaturated acids containing a 1Z,5Z,9Z-triene moiety in 61–64% yields using the new Ti-catalyzed cross-coupling of oxygen-containing and aliphatic 1,2-dienes as the key synthetic step. It was shown for the first time that trienoic acids with non-methylene-interrupted Z-double bonds show moderate cytotoxic activities against tumor cell lines (Jurkat, K562, U937, HL60, HeLa), human embryonic kidney cells (Hek293), normal fibroblasts and human topoisomerase I (hTop1) inhibitory activity in vitro. The synthesized acids efficiently initiate apoptosis of Jurkat tumor cells, with the cell death mechanism being activated by the mitochondrial pathway. A probable mechanism of topoisomerase I inhibition was also hypothesized on the basis of in silico studies resorting to docking. The activation and inhibition of the most versatile intracellular signaling pathways (CREB, JNK, NFkB, p38, ERK1/2, Akt, p70S6K, STAT3 and STAT5 tyrosine kinases) responsible for cell proliferation and for initiation of apoptosis were studied by multiplex assay technology (Luminex xMAP).

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