IPI549 (Eganelisib)

Biological Activity

In vitro: IPI-549 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). IPI549 is evaluated for activity across all Class I PI3K isoforms. The binding affinity of IPI549 for PI3K-γ is determined by measuring the individual rates constants and for PI3K-α, β and δ using equilibrium fluorescent titration. IPI549 is found to be 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, IPI549 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, IPI549 dose dependently inhibits PI3Kγ 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 μM. In vivo: IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ 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-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. IPI-549 significantly reduces neutrophil migration in a dose dependent manner in this model when administered orally at all of the tested doses.

Product Citations

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  Tampere University. 2021.

  Novel Targeted Therapies and Prognostic Markers for T Cell Acute Lymphoblastic Leukemia
  IPI549 (Eganelisib) purchased from AbMole

Chemical Information

Molecular Weight	528.56
Formula	C30H24N8O2
CAS Number	1693758-51-8
Solubility (25°C)	DMSO ≥ 15 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] De Henau O, et al. Nature. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells.

[2] Evans CA, et al. ACS Med Chem Lett. Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate.