Protein kinases represent a very pharmacologically attractive class of targets; however, some members of the family still remain rather unexplored. The biology and therapeutic potential of cdc-like kinases (CLKs) have been explored mainly over the last decade and the first CLK inhibitor, compound SM08502, entered clinical trials only recently. This review summarizes the biological roles and therapeutic potential of CLKs and their heretofore published small-molecule inhibitors, with a focus on the compounds’ potential to be utilized as quality chemical biology probes.
This review provides guidelines for the optimization of proteolysis targeting chimeras (PROTACs) and outlines criteria for their use as chemical probes.
Hydration of proteins profoundly affects their functions. We describe a simple and general method for site-specific analysis of protein hydration based on the in vivo incorporation of fluorescent unnatural amino acids and their analysis by steady-state fluorescence spectroscopy. Using this method, we investigate the hydration of functionally important regions of dehalogenases. The experimental results are compared to findings from molecular dynamics simulations.
The discovery of
clustered regularly interspaced short palindromic
repeats and their associated proteins (Cas) has revolutionized the
field of genome and epigenome editing. A number of new methods have
been developed to precisely control the function and activity of Cas
proteins, including fusion proteins and small-molecule modulators.
Proteolysis-targeting chimeras (PROTACs) represent a new concept using
the ubiquitin-proteasome system to degrade a protein of interest,
highlighting the significance of chemically induced protein-E3 ligase
interaction in drug discovery. Here, we engineered Cas proteins (Cas9,
dCas9, Cas12, and Cas13) by inserting a Phe-Cys-Pro-Phe (FCPF) amino
acid sequence (known as the π-clamp system) and demonstrate
that the modified Cas
FCPF
proteins can be (1) labeled in
live cells by perfluoroaromatics carrying the fluorescein or (2) degraded
by a perfluoroaromatics-functionalized PROTAC (PROTAC-FCPF). A proteome-wide
analysis of PROTAC-FCPF-mediated Cas9
FCPF
protein degradation
revealed a high target specificity, suggesting a wide range of applications
of perfluoroaromatics-induced proximity in the regulation of stability,
activity, and functionality of any FCPF-tagging protein.
Reported is the identification of the furo [3,2b]pyridine core as an ovel scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway.I nitially, ad iverse target compound set was prepared by synthetic sequences based on chemoselective metal-mediated couplings, including assembly of the furo[3,2-b]pyridine scaffold by copper-mediated oxidative cyclization. Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded potent, cell-active,a nd highly selective inhibitors of CLKs.P rofiling of the kinase-inactive subset of 3,5,7-trisubstituted furo[3,2-b]pyridines revealed sub-micromolar modulators of the Hedgehog pathway.
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