Thomas P. Hasaka

Protein-enhanced small molecule disruptors of ordered membrane domains

Katherine M. Stefanski, Geoffrey Li, Dustin D. Luu, Kelvin K. Fosu et autres

Membrane order and fluidity influence many biological processes. However, tools to manipulate membranes under physiological conditions have been limited. In the process of high-throughput screening for molecules that shift the phase partitioning between ordered and disordered membrane phases of the tetraspan membrane …

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BPS2026 – Discovery of a small molecular modulator of the cellular trafficking of the KCNQ1 potassium channel

Charles R. Sanders, Katherine R. Clowes, Carlos G. Vanoye, Ana C Chang-Gonzalez et autres

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Pharmacological tools to modulate ordered membrane domains and order-dependent protein function

Katherine M. Stefanski, Hui Huang, Dustin D. Luu, Geoffrey C. Li et autres

Ordered membrane nanodomains colloquially known as “lipid rafts” have many proposed cellular functions. However, pharmacological tools to modulate protein affinity for rafts and to manipulate raft formation are currently lacking. We screened 24,000 small molecules for compounds that impact the raft affinity …

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High-throughput screening identifies a trafficking corrector for long QT syndrome–associated KCNQ1 variants

Katherine R. Clowes, Carlos G. Vanoye, Ana C Chang-Gonzalez, Ian M. Romaine et autres

Congenital long QT syndrome (LQTS) promotes risk for life-threatening cardiac arrhythmia and sudden death in children and young adults. Pathogenic variants in the voltage-gated potassium channel KCNQ1 are the most frequently discovered genetic cause. Most LQTS-associated KCNQ1 variants cause loss of function …

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Protocol for high-throughput drug screening in 384-well 3D collagen cultures of SC colorectal cancer cells using colony morphology as a readout

Sarah Harmych, Thomas P. Hasaka, Vivian Truong Jones, Joshua A. Bauer et autres

Growth of cells in 3D cultures can more accurately predict in vivo behavior than the traditional 2D culture system, which lacks the complex environment of natural tissue. In this protocol, we provide steps to generate 3D collagen cultures in a 384-well format …

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Abstract 4360792: Cell Painting Based High-Content Phenotypic Screening To Elucidate Kinase Signaling Pathways in BTK-Inhibitor Mediated Atrial Fibrillation

Matthew R. Fleming, Carmen Diaz Verdugo, Christian Egly, Marcia Blair et autres

Introduction: One goal of Precision Cardio-Oncology is to identify and ultimately clinically exploit a fundamental understanding of shared signaling pathways in cardiovascular disease and oncologic processes, such as in BTK inhibitor-mediated atrial fibrillation. In clinical trials, the first-generation BTK inhibitor ibrutinib results …

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High Throughput Screening Identifies a Small Molecule Trafficking Corrector for Long-QT Syndrome Associated KCNQ1 Variants

Katherine R. Clowes, Carlos G. Vanoye, Ana C Chang-Gonzalez, Ian M. Romaine et autres

Congenital long QT syndrome (LQTS) promotes risk for life-threatening cardiac arrhythmia and sudden death in children and young adults. Pathogenic variants in the voltage-gated potassium channel KCNQ1 are the most frequently discovered genetic cause. Most LQTS-associated KCNQ1 variants cause loss-of-function secondary to …

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Pharmacological Tools to Modulate Ordered Membrane Domains and Order-Dependent Protein Function

Katherine M. Stefanski, Hui Huang, Dustin D. Luu, J.M.S. Hutchison et autres

Ordered membrane nanodomains colloquially known as "lipid rafts" have many proposed cellular functions. However, pharmacological tools to modulate protein affinity for rafts and to manipulate raft formation are currently lacking. We screened 24,000 small molecules for compounds that impact the raft affinity …

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3D collagen high-throughput screen identifies drugs that induce epithelial polarity and enhance chemotherapy response in colorectal cancer

Sarah Harmych, Thomas P. Hasaka, Chelsie K. Sievers, Seung Woo Kang et autres

Loss of polarity is a hallmark of cancer, and the related epithelial-to-mesenchymal transition (EMT) phenotype impacts prognosis and therapy outcomes, particularly in colorectal cancer (CRC). However, the mechanisms and drugs that impact EMT-related morphological changes are understudied, due to the complete failure …

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Cell painting based high-content phenotypic screening to elucidate kinase signaling pathways in ibrutinib-mediated atrial fibrillation

Matthew R. Fleming, Christian Egly, Marcia Blair, Thomas P. Hasaka et autres

Abstract Background/Introduction One goal of Precision Cardio-Oncology is to identify and ultimately clinically exploit a fundamental understanding of shared signaling pathways in cardiovascular disease and oncologic processes. One example is ibrutinib, which inhibits BTK (Bruton’s tyrosine kinase) and CSK. While ibrutinib has …

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HIF2 Activation Derails Alveolar Differentiation Through Metabolic, Biosynthetic, and Transcriptional Changes

A. Scott McCall, H. David, Carla L. Calvi, Thomas P. Hasaka et autres

Abstract Rationale: The current paradigm of Idiopathic Pulmonary Fibrosis (IPF) pathogenesis implicates recurrent injury and dysfunctional alveolar epithelial repair as a key driving upstream disease mechanism, yet available IPF treatments do not address key barriers to epithelial regeneration. Recent work has demonstrated …

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Abstract 1223: A novel 3D high-throughput screen identified drugs that re-epithelialize colorectal cancer cells and enhance response to chemotherapy

Sarah Harmych, Thomas P. Hasaka, Chelsie K. Sievers, Sang Yull Kang et autres

Abstract Loss of polarity is a hallmark of cancer, and the related epithelial-to-mesenchymal transition (EMT) phenotype also impacts prognosis and therapy outcomes, particularly in colorectal cancer (CRC). However, the mechanisms and drugs that impact these morphologic changes are understudied, in part, due …

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