Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N-Methylation for PI3Kδ Activity.
Lydia BarnesHollie BlaberDavid T K BrooksLewis ByersDaniel BuckleyZoe C ByronRichard G ChilversLiam CochraneEdward CooneyHeather A DamianLuke FrancisDaniel Fu HeJack M J GraceHarley J GreenEdmund J P HogarthLeyla JusuC Elizabeth KillaleaOliver KingJoseph LambertZoe J LeeNuria S LimaChristina L LongMay-Li MackinnonShusha MahdyJolyon Matthews-WrightMakenzie J MillwardMatthew F MeehanChristopher MerrettLisa MorrisonHal R I ParkeCharlotte PayneLawrence PayneCraig PikeAlexander SealAaron J SeniorKeenan M SmithKamile StanelyteJoe StillibrandRachel SzparaFreya F H TadayAntony M ThreadgouldRohan J TrainorJordan WatersOliver WilliamsCarrie K W WongKatherine WoodNick BartonAnna GruszkaZoe HenleyJames E RowedderRosa CooksonKatherine L JonesAlan NadinIan E SmithSimon J F MacdonaldAndrew NortcliffePublished in: Journal of medicinal chemistry (2019)
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.