Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.

FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development

Decreased Proliferation Kinetics of Mouse Myoblasts Overexpressing FRG1

Although recent publications have linked the molecular events driving facioscapulohumeral muscular dystrophy (FSHD) to expression of the double homeobox transcription factor DUX4, overexpression of FRG1 has been proposed as one alternative causal agent as mice overexpressing FRG1 present with muscular dystrophy. Here, we characterize proliferative defects in two independent myoblast lines overexpressing FRG1. Myoblasts isolated from thigh muscle of FRG1 transgenic mice, an affected dystrophic muscle, exhibit delayed proliferation as measured by decreased clone size, whereas myoblasts isolated from the unaffected diaphragm muscle proliferated normally. To confirm the observation that overexpression of FRG1 could impair myoblast proliferation, we examined C2C12 myoblasts with inducible overexpression of FRG1, finding increased doubling time and G1-phase cells in mass culture after induction of FRG1 and decreased levels of pRb phosphorylation. We propose that depressed myoblast proliferation may contribute to the pathology of mice overexpressing FRG1 and may play a part in FSHD

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors

Blueberry Progress Reports

The 1979 edition of the Blueberry Progress Reports was prepared for the Maine Blueberry Commission and the University of Maine Blueberry Advisory Committee by researchers with the Maine Life Sciences and Agriculture Experiment Station and Maine Cooperative Extension Service at the University of Maine, Orono. Projects in this report include: 1. Cooperative Extension Activities 2. Plan of Work - FY 1980 3. Weed Control in Lowbush Blueberry Fields 4. Pruning of Blueberries 5. Integrated Management of Blueberry Fields 6. Physiology and Culture of the Lowbush Blueberry 7. Effect of Plant-Water Stress on Lowbush Blueberry Growth, Yield and Quality 8. Blueberry Pathology 9. Botrytis Blossom Blight of Lowbush Blueberries 10. Insects Affecting the Blueberr

Bioisosteric discovery of NPA101.3, a second generation RET/VEGFR2 inhibitor optimized for single-agent polypharmacology

RET receptor tyrosine kinase is a driver oncogene in human cancer. We recently identified the clinical drug candidate Pz-1, which targets RET and VEGFR2. A key in vivo metabolite of Pz-1 is its less active demethylated pyrazole analogue. Using bioisosteric substitution methods, here, we report the identification of NPA101.3, lacking the structural liability for demethylation. NPA101.3 showed selective inhibitory profile and an inhibitory concentration 50 (IC50) of <0.001 μM for both RET and VEGFR2. NPA101.3 inhibited phosphorylation of all tested RET oncoproteins as well as VEGFR2 and proliferation of cells transformed by RET. Oral administration of NPA101.3 (10 mg/kg/day) completely prevented formation of tumours induced by RET/C634Y-transformed cells, while it decreased, but did not abrogate, formation of tumours induced by a control oncogene (HRAS/G12V). The balanced synchronous inhibition of both RET and VEGFR2, as well the resistance to demethylation, renders NPA101.3 a potential clinical candidate for RET-driven cancers

Daily 30-min exposure to artificial gravity during 60 days of bed rest does not maintain aerobic exercise capacity but mitigates some deteriorations of muscle function: results from the AGBRESA RCT

Purpose: Spaceflight impairs physical capacity. Here we assessed the protective effect of artificial gravity (AG) on aerobic exercise capacity and muscle function during bed rest, a spaceflight analogue. Methods: 24 participants (33 ± 9 years, 175 ± 9 cm, 74 ± 10 kg, 8 women) were randomly allocated to one of three groups: continuous AG (cAG), intermittent AG (iAG) or control (CTRL). All participants were subjected to 60 days of six-degree head-down tilt bed rest, and subjects of the intervention groups completed 30 min of centrifugation per day: cAG continuously and iAG for 6 × 5 min, with an acceleration of 1g at the center of mass. Physical capacity was assessed before and after bed rest via maximal voluntary contractions, cycling spiroergometry, and countermovement jumps. Results: AG had no significant effect on aerobic exercise capacity, flexor muscle function and isometric knee extension strength or rate of force development (RFD). However, AG mitigated the effects of bed rest on jumping power (group * time interaction of the rmANOVA p < 0.001; iAG − 25%, cAG − 26%, CTRL − 33%), plantar flexion strength (group * time p = 0.003; iAG − 35%, cAG − 31%, CTRL − 48%) and plantar flexion RFD (group * time p = 0.020; iAG − 28%, cAG − 12%, CTRL − 40%). Women showed more pronounced losses than men in jumping power (p < 0.001) and knee extension strength (p = 0.010). Conclusion: The AG protocols were not suitable to maintain aerobic exercise capacity, probably due to the very low cardiorespiratory demand of this intervention. However, they mitigated some losses in muscle function, potentially due to the low-intensity muscle contractions during centrifugation used to avoid presyncope

Whole-Genome Analysis of Diversity and SNP-Major Gene Association in Peach Germplasm

Peach was domesticated in China more than four millennia ago and from there it spread world-wide. Since the middle of the last century, peach breeding programs have been very dynamic generating hundreds of new commercial varieties, however, in most cases such varieties derive from a limited collection of parental lines (founders). This is one reason for the observed low levels of variability of the commercial gene pool, implying that knowledge of the extent and distribution of genetic variability in peach is critical to allow the choice of adequate parents to confer enhanced productivity, adaptation and quality to improved varieties. With this aim we genotyped 1,580 peach accessions (including a few closely related Prunus species) maintained and phenotyped in five germplasm collections (four European and one Chinese) with the International Peach SNP Consortium 9K SNP peach array. The study of population structure revealed the subdivision of the panel in three main populations, one mainly made up of Occidental varieties from breeding programs (POP1OCB), one of Occidental landraces (POP2OCT) and the third of Oriental accessions (POP3OR). Analysis of linkage disequilibrium (LD) identified differential patterns of genome-wide LD blocks in each of the populations. Phenotypic data for seven monogenic traits were integrated in a genome-wide association study (GWAS). The significantly associated SNPs were always in the regions predicted by linkage analysis, forming haplotypes of markers. These diagnostic haplotypes could be used for marker-assisted selection (MAS) in modern breeding programs

Microwave-assisted green synthesis of anilines, phenols, and benzenediamines without transition metals, ligands, or organic solvents

A novel, microwave-assisted method producing anilines and phenols from activated aryl halides is reported. This high-yielding method reduces current reaction requirements and removes organic solvents and catalysts making a more efficient and eco-friendly alternative for the synthesis of important pharmaceutical building blocks. [GRAPHICS] .National Cancer Institute; National Institutes of Health [5F99CA21248002]; University of Arkansas; Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20 GM109005]; [NIH 1R01CA194094-010]; [1R01CA197178-01A1]Open access journal.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]