Dual Inhibition of Bruton's Tyrosine Kinase and Phosphoinositide-3-Kinase p110δ as a Therapeutic Approach to Treat Non-Hodgkin's B Cell Malignancies.

Although new targeted therapies, such as ibrutinib and idelalisib, have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies, or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors, possibly prolonging the duration of the response and reducing resistance. Early clinical trials have tested this approach by dosing two drugs in combination in NHL patients. We discovered a single molecule, MDVN1003 (1-(5-amino-2,3-dihydro-1H-inden-2-yl)-3-(8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), that inhibits Bruton's tyrosine kinase and phosphatidylinositol-3-kinase δ, two proteins regulated by the B cell receptor that drive the growth of many NHLs. In this report, we show that this dual inhibitor prevents the activation of B cells and inhibits the phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2, two downstream mediators that are important for this process. Additionally, MDVN1003 induces cell death in a B cell lymphoma cell line but not in an irrelevant erythroblast cell line. Importantly, we found that this orally bioavailable dual inhibitor reduced tumor growth in a B cell lymphoma xenograft model more effectively than either ibrutinib or idelalisib. Taken together, these results suggest that dual inhibition of these two key pathways by a single molecule could be a viable approach for treatment of NHL patients.

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ.

The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.

Limited and fitness-neutral effects of resource heterogeneity on sociality in a communally rearing rodent.

Contrasting scenarios have been proposed to explain how resource heterogeneity influences group living or sociality. First, sociality may result from individuals in larger groups attaining net fitness benefits by monopolizing access to resources ("resource-defense" hypothesis). Second, sociality may be the fitness-neutral outcome of multiple individuals using a territory with sufficient resources to sustain a group of conspecifics ("resource-dispersion" hypothesis). While previous studies have tended to support the resource-dispersion hypothesis, these analyses have typically examined only 1 or a few predictions, making it difficult to distinguish between the 2 alternatives. We conducted a 4-year field study of Octodon degus to quantify the effects of spatial heterogeneity in food and refuge distributions on group size and 2 components of reproductive success (per capita number of offspring, offspring survival) in this plural breeding and communal rearing rodent. We found only a small effect of heterogeneity of food resources on group size; the effect food resource distribution on group territory size varied across years. Group size did not vary with spatial variation in group territory size and quality. Importantly, there was no covariation between group size and quality of an individual's territory (i.e., a measure of individual access to resources), or between this measure of territory quality and reproductive success, implying no resource-based benefits to social degus. Overall, our results were more consistent with fitness-neutral relationships among spatial heterogeneity of resources, sociality, and territory size. The resource-dispersion hypothesis, however, did not provide a complete explanation for degu socioecology. Se han propuesto distintas hipótesis para explicar cómo la heterogeneidad de los recursos afecta la vida en grupos, o sociabilidad. Esta puede surgir en situaciones donde individuos en grupos grandes se benefician al monopolizar el acceso a recursos (hipótesis de defensa de recursos). Por otra parte, la vida en grupos también puede ser el resultado neutro (en términos de adecuación) de individuos que comparten un territorio con recursos suficientes (hipótesis de dispersión de recursos). Aunque algunos estudios previos han validado la hipótesis de dispersión de recursos, estos solo han evaluado un número limitado de las predicciones de esta hipótesis, lo que ha dificultado distinguir entre esta y otras hipótesis alternativas. Durante un estudio de 4 años cuantificamos los efectos de la heterogeneidad espacial de alimento y distribución de refugios sobre el tamaño de grupo y dos componentes del éxito reproductivo (número per cápita de crías, supervivencia de las crías) en Octodon degus. Se registraron efectos relativamente pequeños de la heterogeneidad espacial del alimento sobre el tamaño de grupo, y variables entre años sobre el tamaño del territorio de cada grupo. El tamaño de grupo no fue afectado por la variación espacial en el tamaño y calidad del territorio de los grupos. No se registró co-variación entre el tamaño de los grupos y la calidad del territorio de cada individuo (una medida individual del acceso a recursos), o entre la calidad del territorio individual y el éxito reproductivo, lo que sugiere ausencia de beneficios derivados del uso social de recursos en degus. En general, los resultados fueron más consistentes con un escenario de efectos neutros de la heterogeneidad espacial de recursos sobre la sociabilidad. Sin embargo, la hipótesis de dispersión de recursos no explicó el conjunto de efectos (o su ausencia) asociados a la socioecología del degu.

Septin 7: actin cross-organization is required for axonal association of Schwann cells.

Myelin sheaths present two distinct domains: compacted myelin spirals and flanking non-compacted cytoplasmic channels, where lipid and protein segregation is established by unknown mechanisms. Septins, a conserved family of membrane and cytoskeletal interacting GTPases, form intracellular diffusion barriers during cell division and neurite extension and are expressed in myelinating cells. Septins, particularly septin 7 (Sept7), the central constituent of septin polymers, are associated with the cytoplasmic channels of myelinating cells. Here we show that Schwann cells deprived of Sept7 fail to wrap around axons from dorsal root ganglion neurons and exhibit disorganization of the actin cytoskeleton. Likewise, Sept7 distribution is dependent on microfilament but not microtubule organization.

Septin 7: Actin cross-organization is required for axonal association of Schwann cells

Myelin sheaths present two distinct domains: compacted myelin spirals and flanking non-compacted cytoplasmic channels, where lipid and protein segregation is established by unknown mechanisms. Septins, a conserved family of membrane and cytoskeletal interacting GTPases, form intracellular diffusion barriers during cell division and neurite extension and are expressed in myelinating cells. Septins, particularly septin 7 (Sept7), the central constituent of septin polymers, are associated with the cytoplasmic channels of myelinating cells. Here we show that Schwann cells deprived of Sept7 fail to wrap around axons from dorsal root ganglion neurons and exhibit disorganization of the actin cytoskeleton. Likewise, Sept7 distribution is dependent on microfilament but not microtubule organization.