Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors

Smith, Andrew J.H.; Pawar, Mercy; Dort, Marcian E. Van; Galbán, Stefanie; Welton, Amanda R.; Thurber, Greg M.; Ross, Brian D.; Besirli, Cagri G.

doi:10.1089/jop.2017.0126

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…A 30-gauge needle was inserted into the mid-vitreous, and 50 μL of 2.3 mM or 23 mM ML-265 was administered intravitreally. Delivery of the compound into the eye was confirmed via clinical inspection 57 . An aqueous humor sample (100 μL) was collected from each eye prior to intravitreal injection to serve as a baseline control.…”

Section: Metabolism Measurementsmentioning

confidence: 99%

Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis

Wubben

Pawar

Weh

et al. 2020

Sci Rep

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Photoreceptor cell death is the ultimate cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective modalities to improve photoreceptor survival. Similar to cancer cells, photoreceptors maintain pyruvate kinase muscle isoform 2 (PKM2) expression, which is a critical regulator in aerobic glycolysis. Unlike PKM1, which has constitutively high catalytic activity, PKM2 is under complex regulation. Recently, we demonstrated that genetically reprogramming photoreceptor metabolism via PKM2-to-PKM1 substitution is a promising neuroprotective strategy. Here, we explored the neuroprotective effects of pharmacologically activating PKM2 via ML-265, a small molecule activator of PKM2, during acute outer retinal stress. We found that ML-265 increased PKM2 activity in 661 W cells and in vivo in rat eyes without affecting the expression of genes involved in glucose metabolism. ML-265 treatment did, however, alter metabolic intermediates of glucose metabolism and those necessary for biosynthesis in cultured cells. Long-term exposure to ML-265 did not result in decreased photoreceptor function or survival under baseline conditions. Notably, though, ML-265-treatment did reduce entrance into the apoptotic cascade in in vitro and in vivo models of outer retinal stress. These data suggest that reprogramming metabolism via activation of PKM2 is a novel, and promising, therapeutic strategy for photoreceptor neuroprotection.

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Section: Metabolism Measurementsmentioning

confidence: 99%

Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis

Wubben

Pawar

Weh

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Delivery of the compound into the eye was confirmed via clinical inspection. 55 An aqueous humor sample (100 μL) was collected from each eye prior to intravitreal injection to serve as a baseline control. A 30-gauge needle on a 1 ml syringe was used to enter the anterior chamber of the eye and aspirate the aqueous humor in a controlled fashion.…”

Section: Methodsmentioning

confidence: 99%

Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, provides photoreceptor neuroprotection

Pawar

et al. 2019

Preprint

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“…La oncogénesis requiere la activación desproporcionada de vías que median procesos celulares; una de la más importante es la MAPK, que incluye activación de proteínas cinasas y están relacionadas con regulación de muerte celular programada 1 . Se requieren medicamentos efectivos que contrarresten los cambios en las vías de señalización y que a su vez sean tolerables por el paciente para que este complete el tratamiento 2 .…”

Section: Introductionunclassified

Toxicidad retiniana inducida por nuevos antineoplásicos. Revisión de la literatura

López-Puerto¹,

Quijano-Nieto²,

Otoya-Albino³

2022

RSCO

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Introducción: Los nuevos antineoplásicos son medicamentos innovadores en el tratamiento del cáncer. Actualmente hay poca información sobre la seguridad y efectos adversos de estos medicamentos a nivel retiniano. Es importante conocer estos efectos para prevenir pérdida de visión en pacientes oncológicos. Objetivo: Definir cuáles son los hallazgos de toxicidad retiniana en los usuarios de nuevos antineoplásicos. Diseño del estudio: Revisión de la literatura. Métodos: Se realizó una búsqueda de literatura en PubMed, Embase, Cochrane, Scielo y literatura gris con términos MeSH: "toxicity" AND "retina" AND "drugs" AND/OR "MEK inhibitors", "BRAF inhibitors", "checkpoint inhibitors". Se seleccionaron 16 artículos para análisis y extracción de datos. Resultados: Existen múltiples efectos adversos reportados en la literatura, los más comunes son desprendimiento de retina exudativo y seroso asociado a la presencia de líquido subretiniano, oclusión de vena central de retina y alteraciones vasculares. La patología más estudiada ha sido melanoma metastásico y la terapia que más presenta efectos adversos ha sido la combinada MEK-BRAF.

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Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors

Abstract: Novel MEK and PI3K bifunctional inhibitors ST-162 and ST-168 demonstrate favorable in vitro and in vivo ocular toxicity profiles, supporting their further development as potential therapeutic agents targeting multiple aggressive tumors.

Cited by 4 publications

References 46 publications

Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis

Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis

Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, provides photoreceptor neuroprotection

Toxicidad retiniana inducida por nuevos antineoplásicos. Revisión de la literatura

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