A5007627344- Receptor Mechanisms and Signaling
- Phosphodiesterase function and regulation
- Advanced Fluorescence Microscopy Techniques
- bioluminescence and chemiluminescence research
- 14-3-3 protein interactions
- Gene Regulatory Network Analysis
- Microtubule and mitosis dynamics
- Photoreceptor and optogenetics research
- Signaling Pathways in Disease
- Ubiquitin and proteasome pathways
- Viral Infectious Diseases and Gene Expression in Insects
- Protein Kinase Regulation and GTPase Signaling
- Lipid Membrane Structure and Behavior
- Circadian rhythm and melatonin
- Computational Drug Discovery Methods
- Machine Learning in Bioinformatics
- Microbial Natural Products and Biosynthesis
- Innovative Microfluidic and Catalytic Techniques Innovation
- Optical Imaging and Spectroscopy Techniques
- Total Knee Arthroplasty Outcomes
- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- Advanced Biosensing Techniques and Applications
- Cancer, Lipids, and Metabolism
- Biofuel production and bioconversion
Pfizer (United States)
2021-2024
University of California, San Diego
2017-2023
University of Virginia
2011-2015
University of Colorado Boulder
2011
Johns Hopkins University
2009
Johns Hopkins Medicine
2009
KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate H3K23 exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of to achieve therapeutic benefit has been a challenge. Here we describe identification highly potent, selective, orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from benzisoxazole series, which demonstrates anti-tumor...
Signaling networks are spatiotemporally organized to sense diverse inputs, process information, and carry out specific cellular tasks. In β cells, Ca 2+ , cyclic adenosine monophosphate (cAMP), Protein Kinase A (PKA) exist in an oscillatory circuit characterized by a high degree of feedback. Here, we describe mode regulation within this involving spatial dependence the relative phase between cAMP, PKA, . We show that mouse MIN6 nanodomain clustering -sensitive adenylyl cyclases (ACs) drives...
### Introduction Cyclic adenosine 3′, 5′-monophosphate (cAMP) is a widely used biochemical messenger, transducing extracellular stimuli into myriad of cellular responses. In the late 1970s, data emerged showing that hormone receptors acting via cAMP have distinct effects on cardiac function.
Photopolymerizable poly(ethylene glycol) (PEG) hydrogels offer a platform to deliver cells in vivo and support three-dimensional cell culture but should be designed degrade sync with neotissue development endure the physiologic environment.We asked whether (1) incorporation of degradation into PEG facilitates tissue comprised essential cartilage macromolecules; (2) early loading before pericellular matrix formation, duration load affects production; (3) dynamic general influences macroscopic...
Objective: Developing a drug requires balancing several factors that define potency, efficacy and pharmacokinetic (PK) properties. Identifying the magnitude duration of target engagement early in development can help focus chemistry design criteria accelerate advancement therapeutics to patients. To assess this process an vitro experimental method was developed coupled with mathematical model elucidate which PK metric (Cmax, Cave, or threshold concentration) best correlates efficacy. This...
A major limitation of time-lapse microscopy combined with fluorescent biosensors, a powerful tool for quantifying spatiotemporal dynamics signaling in single living cells, is low-experimental throughput. To overcome this limitation, we created highly customizable, MATLAB-based platform: flexible automated liquid-handling microscope (FALCOscope) that coordinates an OpenTrons liquid handler and fluorescence to automate drug treatments, imaging, single-cell analysis. test the feasibility...
Abstract One critical component of engineering living tissue equivalents is the design scaffolds (often made hydrogels) whose degradation kinetics can match that matrix production by cells. However, cell-mediated enzymatic a hydrogel highly complex and nonlinear process challenging to comprehend based solely on experimental observations. To address this issue, study presents triphasic mixture model enzyme–hydrogel system, which consists solid polymer network, water enzyme. On basis theory,...
Scaffold proteins localize two or more signaling enzymes in close proximity to their downstream effectors. A-kinase-anchoring (AKAPs) are a canonical family of scaffold known bind protein kinase A (PKA) and other enzymes. Several AKAPs have been shown accelerate, amplify, specify signal transduction dynamically regulate numerous cellular processes. However, there is little theory available mechanistically explain how on scaffolds differs from solution biochemistry. In our present study, we...
By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and first-in-class (FIC) opportunity to provide new impactful therapeutic agent oncology patients. Herein, we describe hit-to-lead optimization effort that resulted the delivery two highly selective MASTL inhibitors. Key strategies leveraged enable this work included structure-based drug design (SBDD), analysis lipophilic efficiency (LipE) synthesis. The...
The ability to observe functional and morphological changes in the brain is critical understanding behavioral developmental neuroscience. With advances electronics miniaturization, electrophysiological recordings from awake, behaving animals has allowed investigators perform a multitude of studies by observing as an animal engaged certain tasks. Imaging offers advantages structure well function, monitor activity over large areas. However, imaging not been explored well. We present design...
Abstract Cell cycle/tumor repressors can be pharmacologically activated to repress uncontrollable proliferation of cancer cells. However, targeting cell cycle regulators G2/M and mitotic checkpoints achieve maximum therapeutic benefit remains a challenge due limited index. Here, we identified highly potent selective oral bioavailable clinical candidate inhibitors the first-in-class oncology target Microtubule Associated Serine/Threonine Kinase-Like (MASTL) aimed at expanding control for...
Time‐lapse microscopy combined with fluorescent biosensors is a powerful tool to quantitatively measure cellular signaling dynamics and observe morphology high spatial temporal resolution. Unfortunately, the collection of these data can be time intensive due serial manual addition small volumes stimulants. While perfusion systems for microscopes automate delivery drugs, they often require relatively large amount drug may limit number different drugs that loaded at given time. To address...
The spatiotemporal fidelity of signal transduction is maintained in large part by scaffolding proteins. In particular, A‐Kinase Anchoring Proteins (AKAPs) accelerate and amplify the phosphorylation substrate proteins anchored kinases. However, mechanisms underlying these phenomena remain unclear. Our present study endeavors to clarify this mechanism utilizing a combination mathematical modeling, biochemistry, FRET microscopy. We propose model wherein enzymes on scaffold undergo...
ABSTRACT Signaling networks are spatiotemporally organized in order to sense diverse inputs, process information, and carry out specific cellular tasks. In pancreatic β cells, Ca 2+ , cyclic adenosine monophosphate (cAMP), Protein Kinase A (PKA) exist an oscillatory circuit characterized by a high degree of feedback, which allows for signaling controls based on the oscillation frequencies. Here, we describe novel mode regulation within this involving spatial dependence relative phase between...
Kinase signaling pathways regulate many cellular processes and are often dysregulated in cancers. The intratumoral heterogeneity of kinase activity the context tumor microenvironment presents a challenge for kinase‐targeted cancer therapeutics. Therefore, characterizing profiles complex environment can help address this challenge. Current genetically encoded fluorescent biosensors have been widely used research. Even with sensitive dynamic readout these biosensors, it is difficult to capture...
Abstract Nomination of new oncology targets has been greatly aided by advances in genetic screening and profiling, but developing potent, selective small molecule inhibitors against these remains a resource intensive pursuit. To significantly de-risk this process we applied chemical biology strategy to model pharmacological inhibition the MASTL kinase showed that enzymatic accurately mimicked targeted perturbation. Specifically, engineered an electrophile-sensitive version through single...