Intracellular pH (pHi) homeostasis is intertwined with a myriad of normal cellular behaviors as well as pathological pro-cesses. As such, small molecule probes for the measurement of pHi are invaluable...
Optimization
of a lead series of PI3Kδ inhibitors based on
a dihydroisobenzofuran core led to the identification of potent, orally
bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ,
and compound 19 was not well-tolerated in a 7-day rat
toxicity study. Structure-based design led to an improvement in selectivity
for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties
resulted in the discovery of compound 41, which showed
improved toxicological outcomes at similar exposure levels to compound 19.
Mitochondrial pH (pHmito) is intimately related to mitochondrial
function, and aberrant values for pHmito are linked to
several disease states. We report the design, synthesis, and application
of mitokyne 1the first small molecule pHmito sensor for stimulated Raman scattering (SRS) microscopy.
This ratiometric probe can determine subtle changes in pHmito in response to external stimuli and the inhibition of both the electron
transport chain and ATP synthase with small molecule inhibitors. In
addition, 1 was also used to monitor mitochondrial dynamics
in a time-resolved manner with subcellular spatial resolution during
mitophagy providing a powerful tool for dissecting the molecular and
cell biology of this critical organelle.
Selective inhibitors of phosphoinositide 3-kinase delta are of interest for the treatment of inflammatory diseases. Initial optimization of a 3-substituted indazole hit compound targeting the kinase PIM1 focused on improving selectivity over GSK3β through consideration of differences in the ATP binding pockets. Continued kinase cross-screening showed PI3Kδ activity in a series of 4,6-disubstituted indazole compounds, and subsequent structure-activity relationship exploration led to the discovery of an indole-containing lead compound as a potent PI3Kδ inhibitor with selectivity over the other PI3K isoforms.
Phosphoinositide-3-kinase
δ (PI3Kδ) is a critical regulator
of cell growth and transformation and has been explored as a therapeutic
target for a range of diseases. Through the exploration of the thienopyrimidine
scaffold, we have identified a ligand-efficient methylation that leads
to remarkable selectivity for PI3Kδ over the closely related
isoforms. Interrogation through the Free–Wilson analysis highlights
the innate selectivity the thienopyrimidine scaffold has for PI3Kδ
and provides a predictive model for the activity against the PI3K
isoforms.
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