IPI-549 (IPI549) is a potent, highly selective, orally active inhibitor of PI3Kγ with IC50 of 16 nM, displays >100-fold selectivity over other lipid and protein kinases (PI3Kα IC50=3.2 uM, PI3Kβ IC50=3.5 uM, PI3Kδ IC50>8.4 uM); demonstrates excellent PI3Kγ potency (IC50=1.2 nM) and selectivity against other Class I PI3K isoforms (>146-fold) in cellular phospho-AKT assays, dose dependently inhibits PI3Kγ dependent bone marrow-derived macrophage (BMDM) migration; demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo.Solid Tumors Phase 1 Clinical(In Vitro):Eganelisib (IPI549) inhibits PI3Kγ with IC50 of 16 nM, with >100-fold selectivity over other lipid and protein kinases (PI3Kα IC50=3.2 μM, PI3Kβ IC50=3.5 μM, PI3Kδ IC50>8.4 μM). Eganelisib is evaluated for activity across all Class I PI3K isoforms. The binding affinity of Eganelisib for PI3K-γ is determined by measuring the individual rates constants and for PI3K-α, β and δ using equilibrium fluorescent titration. Eganelisib is a remarkably tight binder to PI3Kγ with a Kd of 290 pM and >58-fold weaker affinity for other Class I PI3K isoforms (PI3Kα Kd=17 nM, PI3Kβ Kd=82 nM, PI3Kδ Kd=23 M). In PI3K-α, -β, -γ, and -δ dependent cellular phospho-AKT assays, Eganelisib demonstrates excellent PI3K-γ potency (IC50=1.2 nM) and selectivity against other Class I PI3K isoforms (>146-fold). Cellular IC50s for Class I PI3Kα (250 nM), PI3Kβ (240 nM), PI3Kγ (1.2 nM), PI3Kδ (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, Eganelisib dose dependently inhibits PI3Kγ dependent bone marrow-derived macrophage (BMDM) migration. Eganelisib is selective against a panel of 80 GPCRs, ion channels, and transporters at 10 μM.(In Vivo):Eganelisib (IPI549) demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration. In vivo (mice, rats, dog, and monkeys), Eganelisib has excellent oral bioavailability, low clearance, and distributed into tissues with a mean volume of distribution of 1.2 L/kg. Overall, Eganelisib has a favorable pharmacokinetic profile to allow potent and selective inhibition of PI3K-γ 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. Eganelisib significantly reduces neutrophil migration in a dose dependent manner in this model when administered orally at all of the tested doses.
Eganelisib (IPI549) demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration. In vivo (mice, rats, dog, and monkeys), Eganelisib has excellent oral bioavailability, low clearance, and distributed into tissues with a mean volume of distribution of 1.2 L/kg. Overall, Eganelisib has a favorable pharmacokinetic profile to allow potent and selective inhibition of PI3K-γ 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. Eganelisib significantly reduces neutrophil migration in a dose dependent manner in this model when administered orally at all of the tested doses.
In Vitro
Eganelisib (IPI549) inhibits PI3Kγ with IC50 of 16 nM, with >100-fold selectivity over other lipid and protein kinases (PI3Kα IC50 = 3.2 μM, PI3Kβ IC50 = 3.5 μM, PI3Kδ IC50>8.4 μM). Eganelisib is evaluated for activity across all Class I PI3K isoforms. The binding affinity of Eganelisib for PI3K-γ is determined by measuring the individual rates constants and for PI3K-α, β and δ using equilibrium fluorescent titration. Eganelisib is a remarkably tight binder to PI3Kγ with a Kd of 290 pM and >58-fold weaker affinity for other Class I PI3K isoforms (PI3Kα Kd=17 nM, PI3Kβ Kd=82 nM, PI3Kδ Kd=23 M). In PI3K-α, -β, -γ, and -δ dependent cellular phospho-AKT assays, Eganelisib demonstrates excellent PI3K-γ potency (IC50 = 1.2 nM) and selectivity against other Class I PI3K isoforms (>146-fold). Cellular IC50s for Class I PI3Kα (250 nM), PI3Kβ (240 nM), PI3Kγ (1.2 nM), PI3Kδ (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, Eganelisib dose dependently inhibits PI3Kγ dependent bone marrow-derived macrophage (BMDM) migration. Eganelisib is selective against a panel of 80 GPCRs, ion channels, and transporters at 10 μM.
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