WERE U.S. CROP YIELDS RANDOM IN RECENT YEARS?

Crop Production/Industries,

PRICE, YIELD, AND GROSS REVENUE VARIABILITY FOR SELECTED GEORGIA CROPS

Demand and Price Analysis,

BPR1K653, a Novel Aurora Kinase Inhibitor, Exhibits Potent Anti-Proliferative Activity in MDR1 (P-gp170)-Mediated Multidrug-Resistant Cancer Cells

Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments

Evaluation of the antitumor effects of BPR1J-340, a potent and selective FLT3 inhibitor, alone or in combination with an HDAC inhibitor, vorinostat, in AML cancer.

Overexpression or/and activating mutation of FLT3 kinase play a major driving role in the pathogenesis of acute myeloid leukemia (AML). Hence, pharmacologic inhibitors of FLT3 are of therapeutic potential for AML treatment. In this study, BPR1J-340 was identified as a novel potent FLT3 inhibitor by biochemical kinase activity (IC50 approximately 25 nM) and cellular proliferation (GC50 approximately 5 nM) assays. BPR1J-340 inhibited the phosphorylation of FLT3 and STAT5 and triggered apoptosis in FLT3-ITD(+) AML cells. The pharmacokinetic parameters of BPR1J-340 in rats were determined. BPR1J-340 also demonstrated pronounced tumor growth inhibition and regression in FLT3-ITD(+) AML murine xenograft models. The combination treatment of the HDAC inhibitor vorinostat (SAHA) with BPR1J-340 synergistically induced apoptosis via Mcl-1 down-regulation in MOLM-13 AML cells, indicating that the combination of selective FLT3 kinase inhibitors and HDAC inhibitors could exhibit clinical benefit in AML therapy. Our results suggest that BPR1J-340 may be further developed in the preclinical and clinical studies as therapeutics in AML treatments

Chemical structure of BPR1J-340 and BPR1J-097.

<p>BPR1J-340: <i>N</i>1-(3-4-[([(5-ethyl-3-isoxazolyl)amino]carbonylamino)methyl]phenyl-1<i>H</i>-5-pyrazolyl)-4-[(4-methylpiperazino)methyl]benzamide. BPR1J-097: <i>N</i>1-(3-3-[(phenylsulfonyl)amino]phenyl-1<i>H</i>-5-pyrazolyl)-4-(4-methylpiperazino)benzamide.</p

BPR1J-340 inhibits FLT3-dependent signaling.

<p>(<b>A</b>) MV4;11 cells were treated with BPR1J-340 at the indicated concentrations for 1 hour. The phosphorylation status of FLT3 and STAT5 were evaluated by Western blot analysis. (<b>B</b>) HEK 293T cells were transfected with FLT3-WT-, FLT3-ITD-, or FLT3-D835Y-expressing plasmids for 24 hours and then incubated with various concentrations of BPR1J-340 for 1 hour. The FLT3 phosphorylation status in the transfected cells was evaluated by Western blot analysis.</p

BPR1J-340 induces apoptosis in MOLM-13 and MV4;11 cells.

<p>Western blotting revealed that BPR1J-340 was able to induce apoptosis in FLT3-ITD-driven FLT3-ITD⁺ AML cells. MOLM-13 (<b>A</b>) and MV4;11 (<b>B</b>) cells were treated with BPR1J-340 at the indicated concentrations for 24 hours, and the cell lysates were then subjected to Western blot analysis using antibodies against caspase-3 and PARP (poly-ADP-ribose polymerase). (full length caspase-3 (FL-caspase-3), cleavage of caspase-3 (CL-caspase-3), full length poly(ADP-ribose) polymerase (FL-PARP), cleavage of PARP (CL-PARP)).</p

Specificity of kinase inhibition of BPR1J-340.

<p>^a Inhibition of kinase at 100 nM, carried out by Invitrogen SelectScreen® kinase profiling service.</p><p>^b IC50 determination was performed by kinase-Glo assay.</p><p>IC₅₀ determination was performed by Invitrogen SelectScreen® kinase assay.</p><p>Note: IC₅₀ of DBPR1J-340 against multiple oncogenic kinases; the 7 most potent kinases from the 59 kinases screened are shown.</p