Stephen C. Kales
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View article: Mass spectrometry-guided discovery of novel GCPII inhibitor scaffolds
Mass spectrometry-guided discovery of novel GCPII inhibitor scaffolds Open
Introduction There is an unmet need for therapeutics with a novel mechanism to address Q9 symptoms associated with conditions where aberrant glutamatergic neurotransmission is presumed pathogenic. One enzyme of potential relevance is gluta…
View article: KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage
KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage Open
Basal breast cancer is a subtype with a poor prognosis in need of more effective therapeutic approaches. Here we describe a unique role for the KDM4C histone lysine demethylase in KDM4C -amplified basal breast cancers, where KDM4C inhibiti…
View article: Identifying Molecular Properties of Ataxin-2 Inhibitors for Spinocerebellar Ataxia Type 2 Utilizing High-Throughput Screening and Machine Learning
Identifying Molecular Properties of Ataxin-2 Inhibitors for Spinocerebellar Ataxia Type 2 Utilizing High-Throughput Screening and Machine Learning Open
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder marked by cerebellar dysfunction, ataxic gait, and progressive motor impairments. SCA2 is caused by the pathologic expansion of CAG repeats in the ata…
View article: ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer
ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer Open
View article: Development of a high‐throughput dual‐stream liquid chromatography–tandem mass spectrometry method to screen for inhibitors of glutamate carboxypeptidase II
Development of a high‐throughput dual‐stream liquid chromatography–tandem mass spectrometry method to screen for inhibitors of glutamate carboxypeptidase II Open
Rationale Glutamate carboxypeptidase II (GCPII) catalyzes the hydrolysis of N ‐acetylaspartylglutamate (NAAG) to yield glutamate (Glu) and N ‐acetylaspartate (NAA). Inhibition of GCPII has been shown to remediate the neurotoxicity of exces…
View article: Comparative Analysis of Drug-like EP300/CREBBP Acetyltransferase Inhibitors
Comparative Analysis of Drug-like EP300/CREBBP Acetyltransferase Inhibitors Open
The human acetyltransferase paralogues EP300 and CREBBP are master regulators of lysine acetylation whose activity has been implicated in various cancers. In the half-decade since the first drug-like inhibitors of these proteins were repor…
View article: Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes
Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes Open
View article: Comparative analysis of drug-like EP300/CREBBP acetyltransferase inhibitors
Comparative analysis of drug-like EP300/CREBBP acetyltransferase inhibitors Open
The human acetyltransferase paralogs EP300 and CREBBP are master regulators of lysine acetylation whose activity has been implicated in various cancers. In the half-decade since the first drug-like inhibitors of these proteins were reporte…
View article: Figure S1-S4 and Table S1-S2 from KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations
Figure S1-S4 and Table S1-S2 from KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations Open
Figure S1. Responses of different YUMM cell lines to BRAFi treatment; Figure S2. Inhibition of KDM5 family members by shRNA knockdown and pan-KDM5 inhibitors; Figure S3. Subpopulation composition in tumors of different volumes; Figure S4. …
View article: Figure S1-S4 and Table S1-S2 from KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations
Figure S1-S4 and Table S1-S2 from KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations Open
Figure S1. Responses of different YUMM cell lines to BRAFi treatment; Figure S2. Inhibition of KDM5 family members by shRNA knockdown and pan-KDM5 inhibitors; Figure S3. Subpopulation composition in tumors of different volumes; Figure S4. …
View article: Data from KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations
Data from KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations Open
Tumor heterogeneity is a major challenge for cancer treatment, especially due to the presence of various subpopulations with stem cell or progenitor cell properties. In mouse melanomas, both CD34+p75− (CD34+
View article: Data from KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations
Data from KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations Open
Tumor heterogeneity is a major challenge for cancer treatment, especially due to the presence of various subpopulations with stem cell or progenitor cell properties. In mouse melanomas, both CD34+p75− (CD34+
View article: Supplementary Methods from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation
Supplementary Methods from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation Open
Detailed description of methods for computational modeling and analysis.
View article: Supplementary Methods from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation
Supplementary Methods from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation Open
Detailed description of methods for computational modeling and analysis.
View article: Data from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation
Data from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation Open
Oncogenic mutations in the monomeric Casitas B-lineage lymphoma (Cbl) gene have been found in many tumors, but their significance remains largely unknown. Several human c-Cbl (CBL) structures have recently been solved, depicting the…
View article: Supplementary Tables 1 though 7 from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation
Supplementary Tables 1 though 7 from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation Open
Table S1. Classification of mutations and definition of different classes. Table S2. P-values for different null hypotheses calculated by two-sample t-test. Table S3. Top 25% cancer mutations with the largest energy changes for each state …
View article: Supplementary Tables 1 though 7 from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation
Supplementary Tables 1 though 7 from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation Open
Table S1. Classification of mutations and definition of different classes. Table S2. P-values for different null hypotheses calculated by two-sample t-test. Table S3. Top 25% cancer mutations with the largest energy changes for each state …
View article: Data from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation
Data from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation Open
Oncogenic mutations in the monomeric Casitas B-lineage lymphoma (Cbl) gene have been found in many tumors, but their significance remains largely unknown. Several human c-Cbl (CBL) structures have recently been solved, depicting the…
View article: Supplementary Figures 1 though 6 from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation
Supplementary Figures 1 though 6 from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation Open
Fig. S1. The distribution of unfolding and binding free energy changes for Single, Recurrent and Random class mutations for all states in CBL activation cycle. Fig.S2. The distribution of local RMSD of mutant structures for Single, Recurre…
View article: Supplementary Figures 1 though 6 from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation
Supplementary Figures 1 though 6 from Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation Open
Fig. S1. The distribution of unfolding and binding free energy changes for Single, Recurrent and Random class mutations for all states in CBL activation cycle. Fig.S2. The distribution of local RMSD of mutant structures for Single, Recurre…
View article: Revealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor
Revealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor Open
View article: A quantitative high-throughput screen identifies compounds that lower expression of the SCA2-and ALS-associated gene ATXN2
A quantitative high-throughput screen identifies compounds that lower expression of the SCA2-and ALS-associated gene ATXN2 Open
CAG repeat expansions in the ATXN2 (ataxin-2) gene can cause the autosomal dominant disorder spinocerebellar ataxia type 2 (SCA2) as well as increase the risk of ALS. Abnormal molecular, motor, and neurophysiological phenotypes in SCA2 mou…
View article: Suite of TMPRSS2 Assays for Screening Drug Repurposing Candidates as Potential Treatments of COVID-19
Suite of TMPRSS2 Assays for Screening Drug Repurposing Candidates as Potential Treatments of COVID-19 Open
SARS-CoV-2 is the causative viral pathogen driving the COVID-19 pandemic that prompted an immediate global response to the development of vaccines and antiviral therapeutics. For antiviral therapeutics, drug repurposing allows for rapid mo…
View article: A Suite of TMPRSS2 Assays for Screening Drug Repurposing Candidates as Potential Treatments of COVID-19
A Suite of TMPRSS2 Assays for Screening Drug Repurposing Candidates as Potential Treatments of COVID-19 Open
SARS-CoV-2 is the causative viral pathogen driving the COVID-19 pandemic that prompted an immediate global response to the development of vaccines and antiviral therapeutics. For antiviral therapeutics, drug repurposing allowed for rapid m…
View article: The AKT modulator A-443654 reduces α-synuclein expression and normalizes ER stress and autophagy
The AKT modulator A-443654 reduces α-synuclein expression and normalizes ER stress and autophagy Open
View article: An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19
An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19 Open
SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic. Consequently, much research has gone into the development of preclinical assays for the discovery of new or repurposing of FDA-approved therapies. Preventing viral entry…
View article: An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19
An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19 Open
SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic. Consequently, much research has gone into the development of pre-clinical assays for the discovery of new or repurposing of FDA-approved therapies. Preventing viral entr…
View article: An OpenData portal to share COVID-19 drug repurposing data in real time
An OpenData portal to share COVID-19 drug repurposing data in real time Open
The National Center for Advancing Translational Sciences (NCATS) has developed an online open science data portal for its COVID-19 drug repurposing campaign – named OpenData – with the goal of making data across a range of SARS-CoV-2 relat…
View article: Loss of function Cbl-c mutations in solid tumors
Loss of function Cbl-c mutations in solid tumors Open
Receptor Tyrosine Kinase (RTK) signaling is essential for normal biological processes and disruption of this regulation can lead to tumor initiation and progression. Cbl proteins (Cbl, Cbl-b and Cbl-c) are a family of RING finger (RF) ubiq…
View article: KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance
KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance Open