Doublecortin like kinase 1 (DCLK1) is an understudied kinase that is upregulated in a wide range of cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about its potential as a therapeutic target. We leveraged chemoproteomic profiling and structure-based design to develop the first selective,
in vivo
-compatible chemical probe of the DCLK1 kinase domain, DCLK1-IN-1. We demonstrate activity of DCLK1-IN-1 against clinically relevant patient-derived PDAC organoid models and use a combination of RNA sequencing, proteomics and phosphoproteomics analysis to reveal that DCLK1 inhibition modulates proteins and pathways associated with cell motility in this context. DCLK1-IN-1 will serve as a versatile tool to investigate DCLK1 biology and establish its role in cancer.
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
Frequent
exposure to chemicals in the environment, diet, and endogenous
electrophiles leads to chemical modification of DNA and the formation
of DNA adducts. Some DNA adducts can induce mutations during cell
division and, when occurring in critical regions of the genome, can
lead to the onset of disease, including cancer. The targeted analysis
of DNA adducts over the past 30 years has revealed that the human
genome contains many types of DNA damages. However, a long-standing
limitation in conducting DNA adduct measurements has been the inability
to screen for the total complement of DNA adducts derived from a wide
range of chemicals in a single assay. With the advancement of high-resolution
mass spectrometry (MS) instrumentation and new scanning technologies,
nontargeted “omics” approaches employing data-dependent
acquisition and data-independent acquisition methods have been established
to simultaneously screen for multiple DNA adducts, a technique known
as DNA adductomics. However, notable challenges in data processing
must be overcome for DNA adductomics to become a mature technology.
DNA adducts occur at low abundance in humans, and current softwares
do not reliably detect them when using common MS data acquisition
methods. In this perspective, we discuss contemporary computational
tools developed for feature finding of MS data widely utilized in
the disciplines of proteomics and metabolomics and highlight their
limitations for conducting nontargeted DNA-adduct biomarker discovery.
Improvements to existing MS data processing software and new algorithms
for adduct detection are needed to develop DNA adductomics into a
powerful tool for the nontargeted identification of potential cancer-causing
agents.
Here we report the structure-activity relationship (SAR) investigations of QL-XII-47 (QL47), a compound that possesses broad-spectrum antiviral activity against dengue virus and other RNA viruses. A medicinal chemistry campaign initiated from QL47, a previously reported covalent BTK inhibitor, to derive YKL-04-085, which is devoid of any kinase activity when screened against a panel of 468 kinases and with improved pharmacokinetic properties. Both QL47 and YKL-04-085 are potent inhibitors of viral translation and exhibit cellular antiviral activity at 35-fold lower concentrations relative to inhibition of host-cell proliferation.
Selective small-molecule inhibitors of protein kinases can serve as powerful tools to elucidate biological function. Efforts to develop potential drug candidates have yielded a wealth of kinase inhibitors. However, selecting the optimal kinase inhibitor for a particular application can be challenging. While the optimal inhibitor will be application specific, we have attempted to summarize some of the best reported inhibitors for various kinases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.