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
Synthesis and Structure–Activity Relationships of Indazole Arylsulfonamides as Allosteric CC-Chemokine Receptor 4 (CCR4) Antagonists
A series
of indazole arylsulfonamides were synthesized and examined
as human CCR4 antagonists. Methoxy- or hydroxyl- containing groups
were the more potent indazole C4 substituents. Only small groups were
tolerated at C5, C6, or C7, with the C6 analogues being preferred.
The most potent <i>N</i>3-substituent was 5-chlorothiophene-2-sulfonamide. <i>N</i>1 <i>meta</i>-substituted benzyl groups possessing
an α-amino-3-[(methylamino)Âacyl]– group were the most
potent <i>N</i>1-substituents. Strongly basic amino groups
had low oral absorption in vivo. Less basic analogues, such as morpholines,
had good oral absorption; however, they also had high clearance. The
most potent compound with high absorption in two species was analogue <b>6</b> (GSK2239633A), which was selected for further development.
Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric
site denoted site II. X-ray diffraction studies on two indazole sulfonamide
fragments suggested the presence of an important intramolecular interaction
in the active conformation