2 research outputs found
HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins
Small molecule-induced
protein degradation is an attractive strategy
for the development of chemical probes. One method for inducing targeted
protein degradation involves the use of PROTACs, heterobifunctional
molecules that can recruit specific E3 ligases to a desired protein
of interest. PROTACs have been successfully used to degrade numerous
proteins in cells, but the peptidic E3 ligase ligands used in previous
PROTACs have hindered their development into more mature chemical
probes or therapeutics. We report the design of a novel class of PROTACs
that incorporate small molecule VHL ligands to successfully degrade
HaloTag7 fusion proteins. These HaloPROTACs will inspire the development
of future PROTACs with more drug-like properties. Additionally, these
HaloPROTACs are useful chemical genetic tools, due to their ability
to chemically knock down widely used HaloTag7 fusion proteins in a
general fashion
Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy
Inhibition of Itk potentially constitutes
a novel, nonsteroidal
treatment for asthma and other T-cell mediated diseases. In-house
kinase cross-screening resulted in the identification of an aminopyrazole-based
series of Itk inhibitors. Initial work on this series highlighted
selectivity issues with several other kinases, particularly AurA and
AurB. A template-hopping strategy was used to identify a series of
aminobenzothiazole Itk inhibitors, which utilized an inherently more
selective hinge binding motif. Crystallography and modeling were used
to rationalize the observed selectivity. Initial exploration of the
SAR around this series identified potent Itk inhibitors in both enzyme
and cellular assays