Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació

Targeting treatment resistance in breast cancer subtypes via LMTK3 inhibition

Introduction: LMTK3 is an oncogenic Receptor Tyrosine Kinase (RTK) implicated in resistance to endocrine therapy in breast cancer. Initially, LMTK3 was described as a regulator of Estrogen Receptor alpha (ERα) since it was found able to protect it from ubiquitin-mediated proteasomal degradation. In a cohort of breast cancer (BC) patients (n>600), LMTK3 protein levels and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapy. These data were validated in an Asian cohort in which it was shown that LMTK3 was associated with more aggressive tumours. In addition, LMTK3 was demonstrated to contribute in BC invasion and migration. Recently, a new scaffolding function of LMTK3 was described that results in cancer progression through chromatin remodelling. Aim: This study aims to identify selective LMTK3 inhibitors that can be used to enable pathway investigation and establish onward tractability of these compounds for future translational activities. Materials and methods: The Bellbrook Laboratories Transcreener® assay kit was employed and 30,000 compounds were screened to detect novel LMTK3 inhibitors. Nearly 100 of them significantly inhibited LMTK3 activity and were therefore chosen for 10-point concentration-response profiling in duplicate and LC-MS analysis. The top 50 test compounds were clustered into unique chemotypes and were further tested using radiolabelled in vitro kinase assays. The top 5 compounds from two chemotypes were selected to be evaluated with hit-to-lead medicinal chemistry. Subsequently, an active site-directed competition binding assay (DiscoveRx KINOMEscan) was used to quantitatively measure the interactions between the top 5 hit compounds and more than 450 purified human kinases and disease relevant mutant variants. Results and discussion: Two (C28 and C36) out of the 30,000 compounds that were screened inhibited by >95% the activity of only 10 and 8 kinases respectively. Moreover, the S(35) selectivity index of C28 was 0.186 while the selectivity index of C36 was 0.114. Interestingly, quantitative analysis of 38 kinase inhibitors currently used in clinical oncology showed a comparably low S(35) score as C28 and C36. It is expected that the crystallization of the LMTK3 kinase domain that is currently being conducted as well as co-crystallization experiments with these inhibitors and other analogues will guide a rational optimisation strategy of each chemotype. Conclusion: More work is required; however, these data represent a step towards the development of the first LMTK3 inhibitors that may have potential for broad clinical utility in breast cancer

Targeting Treatment Resistance in Breast Cancer Subtypes via LMTK3 Inhibition

Introduction: LMTK3 is an oncogenic Receptor Tyrosine Kinase (RTK) implicated in resistance to endocrine therapy in breast cancer. Initially, LMTK3 was described as a regulator of Estrogen Receptor alpha (ERα) since it was found able to protect it from ubiquitin-mediated proteasomal degradation. In a cohort of breast cancer (BC) patients (n>600), LMTK3 protein levels and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapy. These data were validated in an Asian cohort in which it was shown that LMTK3 was associated with more aggressive tumours. In addition, LMTK3 was demonstrated to contribute in BC invasion and migration. Recently, a new scaffolding function of LMTK3 was described that results in cancer progression through chromatin remodelling. Aim: This study aims to identify selective LMTK3 inhibitors that can be used to enable pathway investigation and establish onward tractability of these compounds for future translational activities. Materials and methods: The Bellbrook Laboratories Transcreener® assay kit was employed and 30,000 compounds were screened to detect novel LMTK3 inhibitors. Nearly 100 of them significantly inhibited LMTK3 activity and were therefore chosen for 10-point concentration-response profiling in duplicate and LC-MS analysis. The top 50 test compounds were clustered into unique chemotypes and were further tested using radiolabelled in vitro kinase assays. The top 5 compounds from two chemotypes were selected to be evaluated with hit-to-lead medicinal chemistry. Subsequently, an active site-directed competition binding assay (DiscoveRx KINOMEscan) was used to quantitatively measure the interactions between the top 5 hit compounds and more than 450 purified human kinases and disease relevant mutant variants. Results and discussion: Two (C28 and C36) out of the 30,000 compounds that were screened inhibited by >95% the activity of only 10 and 8 kinases respectively. Moreover, the S(35) selectivity index of C28 was 0.186 while the selectivity index of C36 was 0.114. Interestingly, quantitative analysis of 38 kinase inhibitors currently used in clinical oncology showed a comparably low S(35) score as C28 and C36. It is expected that the crystallization of the LMTK3 kinase domain that is currently being conducted as well as co-crystallization experiments with these inhibitors and other analogues will guide a rational optimisation strategy of each chemotype. Conclusion: More work is required; however, these data represent a step towards the development of the first LMTK3 inhibitors that may have potential for broad clinical utility in breast cancer

Deazaflavin inhibitors of TDP2 with cellular activity can affect etoposide influx and/or efflux

Tyrosyl DNA phosphodiesterase 2 (TDP2) facilitates the repair of topoisomerase II (TOP2)-linked DNA double-strand breaks and, as a consequence, is required for cellular resistance to TOP2 “poisons”. Recently, a deazaflavin series of compounds were identified as potent inhibitors of TDP2, in vitro. Here, however, we show that while some deazaflavins can induce cellular sensitivity to the TOP2 poison etoposide, they do so independently of TDP2 status. Consistent with this, both the cellular level of etoposide-induced TOP2 cleavage complexes and the intracellular concentration of etoposide was increased by incubation with deazaflavin, suggesting an impact of these compounds on etoposide uptake/efflux. In addition, deazaflavin failed to increase the level of TOP2 cleavage complexes or sensitivity induced by m-AMSA, which is a different class of TOP2 poison to which TDP2-defective cells are also sensitive. In conclusion, while deazaflavins are potent inhibitors of TDP2 in vitro, their limited cell permeability and likely interference with etoposide influx/efflux limits their utility in cells

5-phenyl-4-methyl-thiazol-2-yl-amine derivatives as inhibitors of phosphatidylinositol 3 kinase enzymes (pi3) for the treatment of inflammatory airway diseases

Compounds of Formula (I) in free or salt form, wherein Ra, Rb, R2, R3, R4 and R5 have the meanings as indicated in the specification, are useful for treating conditions that are mediated by mediated by phosphatidylinositol 3-kinase such as inflammatory airway diseases. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described

Development of autotaxin inhibitors: A series of tetrazole cinnamides

A series of inhibitors of Autotaxin (ATX) have been developed from a high throughput screening hit, 1a, which shows an alternative binding mode to known catalytic site inhibitors. Selectivity over the hERG channel and microsomal clearance were dependent on the lipophilicity of the compounds, and this was optimised by reduction of clogD whilst maintaining high affinity ATX inhibition. Compound 15a shows good oral exposure, and concentration dependent inhibition of formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic (PK/PD) experiment

Development of Autotaxin Inhibitors Part 1: A Series of Zinc Binding Triazoles

A series of inhibitors of Autotaxin (ATX) has been developed using the binding mode of known inhibitor, PF 8380, as a template. Replacement of the benzoxazolinone with a triazole zinc-binding motif reduced crystallinity and improved solubility relative to PF-8380. Modification of the linker region removed hERG activity and led to compound 12 - a selective, high affinity, orally-bioavailable inhibitor of ATX. Compound 12 concentration dependently inhibits autotaxin and formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic experiment

Development of isoform selective PI3-kinase inhibitors as pharmacological tools for elucidating the PI3K pathway

Using a parallel synthesis approach to target a non-conserved region of the PI3K catalytic domain a pan-PI3K inhibitor 1 was elaborated to provide alpha, delta and gamma isoform selective Class I PI3K inhibitors 21, 24, 26 and 27. The compounds had good cellular activity and were selective against protein kinases and other members of the PI3K superfamily including mTOR and DNA-PK