Showing papers by "John Stuart Mill published in 2023"

Abstract 5019: Next-generation DYRK1A inhibitors as a new therapeutic approach for the treatment of hematological malignancies

Abstract: Background: The dual-specificity tyrosine-regulated kinase 1A (DYRK1A) can phosphorylate multiple targets involved in key cellular processes that have been associated with the hallmarks of cancer, including proliferation, survival, cell cycle regulation and the DNA damage response1. In addition, compounds that inhibit DYRK1A have demonstrated anti-tumor activity both in vitro and in vivo. However, until recently, there was a paucity of potent, specific, and bioavailable DYRK1A inhibitors that did not target the related cdc2-like kinases (CLKs) and glycogen synthase kinase 3β. In this study, we describe a set of next-generation DYRK1A inhibitors and used them to evaluate the specific contribution of DYRK1A activity to tumor biology and evaluate the therapeutic potential of DYRK1A inhibition in cancer. Methods: DYRK1A expression was analyzed in The Cancer Genome Atlas and Cancer Cell Line Encyclopedia databases. Cancer cell growth dependencies were evaluated by DepMap analysis. Cell-based target engagement (TE) was assessed by NanoBRETTM. Cell viability was assayed with CellTiter-Glo® following 4-day treatment with DYRK1A inhibitors. Synergy was calculated using Chalice software. Pharmacokinetics (PK) were evaluated in rodents and Tumor Growth Inhibition (TGI) in nude mice. Preliminary toxicology was assessed in a 14 day rat study. Results: DYRK1A expression and a systematic DYRK dependencies analysis in human cancers revealed that hematological malignancies, Small Cell Lung and Ovarian cancers rely on DYRK1A expression for their proliferation. A series of potent (biochemical IC50s 3nM to 10nM, TE 19 nM to 134 nM) and highly selective ATP-competitive DYRK1A inhibitors were designed with minimal inhibition of the rest of the kinome (1%-2.3% of kinases inhibited > 90%) Cancer cell lines (n=160) were treated with DYRK1A inhibitors and those belonging to hematological lineages were among the most sensitive (P<0.01). In vitro combination of DYRK1A inhibitors with the anti-leukemia agent venetoclax revealed high synergy in 3 out of the 5 AML cell lines tested (synergy score >20). Compounds that showed good oral bioavailability and plasma exposures in rodents were selected for further characterization in vivo. In the MV-4-11 xenograft model, mice treated daily with 25mg/kg, or 50mg/kg of 2 different DYRK1A showed 72-99% TGI compared to vehicle. Preclinical toxicity profile in rats showed next generation DYRK1A inhibitors were well tolerated. Concluding Remarks: these studies support further evaluation of DYRK1A inhibitors as a therapeutic strategy for some cancers, especially hematological malignancies including AML. 1 Boni, J.; Rubio-Perez, C.; López-Bigas, N.; Fillat, C.; de la Luna, S. The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities. Cancers 2020, 12, 2106. https://doi.org/10.3390/cancers12082106 Citation Format: Matthew C. Jarvis, Gopi Mittapalli, Emily Creger, Chelsea Nora, Maureen Ibanez, Deepti Bhat, Brian Hofilena, Josh Stewart, Elizabeth A. McMillan, Hadi Falahatpisheh, Chi-Ching Mak, Michael White, John S. Hill, Carine Bossard. Next-generation DYRK1A inhibitors as a new therapeutic approach for the treatment of hematological malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5019.

Ganancias capitalistas

Abstract: Este breve ensayo hace una reflexión acerca de la definición de la ganancia de los capitalistas y la relación con la oferta y la demanda, así como el trabajo y los trabajadores. Ésta se genera gracias a la fuerza productiva del trabajo. Asimismo, estudia el vínculo con la remuneración de los trabajadores y hace una importante distinción entre salarios y costo de trabajo, también explica los criterios para determinar cada uno.