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Videos de Conceptos Relacionados

The Ras Gene02:38

The Ras Gene

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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
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Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
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Abnormal Proliferation02:23

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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
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MAPK Signaling Cascades01:07

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Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
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Interactions Between Signaling Pathways

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Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Inhibidores pan-RAS de moléculas pequeñas multivalentes

Matthew E Welsch1, Anna Kaplan2, Jennifer M Chambers2

  • 1Department of Chemistry, Columbia University, New York, NY 10027, USA.

Cell
|February 25, 2017
PubMed
Resumen
Este resumen es generado por máquina.

Los investigadores desarrollaron una nueva molécula pequeña que se dirige a las proteínas RAS, mostrando actividad antitumoral en modelos preclínicos. Este inhibidor pan-RAS demuestra potencial como una nueva estrategia terapéutica para el cáncer.

Palabras clave:
La GTPasaHrasNo lo sé.Las NrasRas también.el cáncerBiología químicadiseño de fármacosy multivalentemolécula pequeña

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Área de la Ciencia:

  • Química medicinal
  • En el campo de la oncología
  • Biología molecular

Sus antecedentes:

  • Las interacciones proteína-proteína (IPP) son cruciales en la señalización celular, y su interrupción ofrece un potencial terapéutico.
  • Las proteínas RAS son reguladores clave del crecimiento celular, y sus mutaciones oncogénicas impulsan muchos cánceres.
  • Dirigirse a las interacciones de los efectores RAS con moléculas pequeñas es una estrategia prometedora para el tratamiento del cáncer.

Objetivo del estudio:

  • Diseñar y sintetizar nuevas moléculas pequeñas dirigidas a proteínas RAS oncogénicas.
  • Evaluar la afinidad de unión y los efectos celulares de estos ligandos pan-RAS.
  • Evaluar el potencial terapéutico de un compuesto de plomo en modelos preclínicos de cáncer.

Principales métodos:

  • Diseño basado en la estructura de pequeñas moléculas dirigidas a sitios adyacentes en el KRAS oncogénico.
  • Síntesis y caracterización de posibles ligandos pan-RAS.
  • Validación biofísica de la unión de los compuestos mediante termoforesis a microescala, RMN y CTI.
  • Evaluación de la letalidad celular y la estabilidad metabólica.
  • Evaluación de la actividad antitumoral en modelos de ratón xenotransplantado.

Principales resultados:

  • Un compuesto, 3144, demostró la unión a las proteínas RAS a través de múltiples técnicas biofísicas.
  • El compuesto 3144 indujo la letalidad en células cancerosas con dependencia de RAS.
  • El compuesto exhibió estabilidad metabólica en los microsomas hepáticos.
  • Se observó una actividad antitumoral significativa en modelos de cáncer de ratón xenotransplantado.

Conclusiones:

  • La inhibición pan-RAS representa una estrategia terapéutica viable para ciertos tipos de cáncer.
  • Los inhibidores multivalentes diseñados utilizando enfoques basados en la estructura pueden dirigirse efectivamente a las superficies de las proteínas.
  • Las pequeñas moléculas dirigidas a las proteínas RAS son prometedoras para futuros tratamientos contra el cáncer.