Mitsunori Kato

In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury

H. Rachel Lagiakos, Yefen Zou, Hideyuki Igawa, Éric Therrien et autres

Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer’s, …

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In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury

H. Rachel Lagiakos, Yefen Zou, Hideyuki Igawa, Éric Therrien et autres

Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, …

us (code pays fourni par la source)

In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury

H. Rachel Lagiakos, Yefen Zou, Hideyuki Igawa, Éric Therrien et autres

Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, …

us (code pays fourni par la source)

In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury

H. Rachel Lagiakos, Yefen Zou, Hideyuki Igawa, Éric Therrien et autres

Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, …

us (code pays fourni par la source)

In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury

H. Rachel Lagiakos, Yefen Zou, Hideyuki Igawa, Éric Therrien et autres

Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, …

us (code pays fourni par la source)

Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma

Michael Visser, Julien P. N. Papillon, Michael J. Luzzio, Matthew J. LaMarche et autres

Uveal melanoma (UM) is the most common primary intraocular malignancy in the adult eye. Despite the aggressive local management of primary UM, the development of metastases is common with no effective treatment options for metastatic disease. Genetic analysis of UM samples reveals …

A Computational Physics-based Approach to Predict Unbound Brain-to-Plasma Partition Coefficient, K p,uu

Morgan Lawrenz, Mats Svensson, Mitsunori Kato, Karen H. Dingley et autres

The blood–brain barrier (BBB) plays a critical role in preventing harmful endogenous and exogenous substances from penetrating the brain. Optimal brain penetration of small-molecule central nervous system (CNS) drugs is characterized by a high unbound brain/plasma ratio (K p,uu ). While various …

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A Computational Physics-based Approach to Predict Unbound Brain-to-Plasma Partition Coefficient, Kp,uu

Morgan Lawrenz, Mats Svensson, Mitsunori Kato, Karen H. Dingley et autres

The blood-brain barrier (BBB) plays a critical role in preventing harmful endogenous and exogenous substances from penetrating the brain. Optimal brain penetration of small molecule CNS drugs is characterized by a high unbound brain/plasma ratio (Kp,uu). While various medicinal chemistry strategies and …

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Combined Free-Energy Calculation and Machine Learning Methods for Understanding Ligand Unbinding Kinetics

Magd Badaoui, Pedro J. Buigues, Dénes Berta, Gaurav Madappa Mandana et autres

The determination of drug residence times, which define the time an inhibitor is in complex with its target, is a fundamental part of the drug discovery process. Synthesis and experimental measurements of kinetic rate constants are, however, expensive and time consuming. In …

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Combined free energy calculation and machine learning methods for understanding ligand unbinding kinetics

Magd Badaoui, Pedro J. Buigues, Dénes Berta, Gaurav Madappa Mandana et autres

ABSTRACT The determination of drug residence times, which define the time an inhibitor is in complex with its target, is a fundamental part of the drug discovery process. Synthesis and experimental measurements of kinetic rate constants are, however, expensive, and time-consuming. In …

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Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer

Matthew J. LaMarche, Michael G. Acker, Andreea Argintaru, Daniel P. Bauer et autres

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as …

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Structure–Activity Relationship Evaluation of Wasp Toxin β-PMTX Leads to Analogs with Superior Activity for Human Neuronal Sodium Channels

Catherine E. Garrison, Wendy Guan, Mitsunori Kato, Thomas J. Tamsett et autres

Beta-pompilidotoxin (β-PMTX) is a 13-amino acid wasp venom peptide that activates human neuronal sodium channel Na V 1.1 with weak activity (40% activation at 3.3 μM of β-PMTX). Through rational design of β-PMTX analogs, we have identified peptides with significantly improved activity …

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