IPI549

In vitro: IPI-549 inhibits PI3Kgamma with IC50 of 16 nM, with > 100-fold selectivity over other lipid and protein kinases (PI3Kalpha IC50=3.2 uM, PI3Kbeta IC50=3.5 uM, PI3Kdelta IC50> 8.4 uM). IPI549 is evaluated for activity across all Class I PI3K isoforms. The binding affinity of IPI549 for PI3K-gamma is determined by measuring the individual rates constants and for PI3K-alpha, beta and delta using equilibrium fluorescent titration. IPI549 is found to be a remarkably tight binder to PI3Kgamma with a Kd of 290 pM and > 58-fold weaker affinity for other Class I PI3K isoforms (PI3Kalpha Kd=17 nM, PI3Kbeta Kd=82 nM, PI3Kdelta Kd=23 M). In PI3K-alpha, -beta, -gamma, and -delta dependent cellular phospho-AKT assays, IPI549 demonstrates excellent PI3K-gamma potency (IC50=1.2 nM) and selectivity against other Class I PI3K isoforms (> 146-fold). Cellular IC50s for Class I PI3Kalpha (250 nM), PI3Kbeta (240 nM), PI3Kgamma (1.2 nM), PI3Kdelta(180 nM) are determined in SKOV-3, 786-O, RAW 264.7, and RAJI cells, respectively, by monitoring inhibition of pAKT S473 by ELISA. Furthermore, IPI549 dose dependently inhibits PI3Kgamma dependent bone marrow-derived macrophage (BMDM) migration. IPI549 is also found to be selective against a panel of 80 GPCRs, ion channels, and transporters at 10 uM. In vivo: IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-gamma mediated neutrophil migration. In vivo (mice, rats, dog, and monkeys), IPI-549 has excellent oral bioavailability, low clearance, and distributed into tissues with a mean volume of distribution of 1.2 L/kg. Overall, IPI-549 has a favorable pharmacokinetic profile to allow potent and selective inhibition of PI3K-gamma in vivo. The t1/2 of IPI-549 for mouse, rat, dog and monkey is 3.2, 4.4, 6.7 and 4.3 h, respectively. IPI-549 significantly reduces neutrophil migration in a dose dependent manner in this model when administered orally at all of the tested doses.

528, 56

15 mg/mL in DMSO