Eganelisib (IPI-549)

Name: Eganelisib (IPI-549)
Brand: Selleck Chemicals
SKU: S8330
Rating: 5 (10 reviews)

For research use only.

Catalog No.S8330

10 publications

CAS No. 1693758-51-8

Eganelisib (IPI-549) is a potent inhibitor of PI3K-γ with >100-fold selectivity over other lipid and protein kinases. The biochemical IC50 for PI3K-γ is 16 nM.

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Biological Activity

Description

Eganelisib (IPI-549) is a potent inhibitor of PI3K-γ with >100-fold selectivity over other lipid and protein kinases. The biochemical IC50 for PI3K-γ is 16 nM.

Targets

PI3Kγ ^[1]
(Cell-free assay)

16 nM

In vitro

IPI-549 is found to be a remarkably tight binder to PI3K-γ with a Kd of 290 pM and >58-fold weaker affinity for other Class I PI3K isoforms. It does not significantly inhibit a panel of 468 mutant and nonmutant protein and lipid kinases (including Class II PI3K isoforms) at 1 μM. In PI3K-α, -β, -γ, and -δ dependent cellular phospho-AKT assays, IPI-549 demonstrates excellent PI3K-γ potency (IC50 = 1.2 nM) and selectivity against other Class I PI3K isoforms (>146-fold). Furthermore, IPI-549 dose dependently inhibits PI3K-γ-dependent bone marrow-derived macrophage (BMDM) migration in vitro. IPI-549 is also found to be selective against a panel of 80 GPCRs, ion channels, and transporters at 10 μM. In vitro, IPI-549 shows moderate to high cell permeability across Caco-2 cell monolayers, is slowly metabolized in cultured hepatocytes (t1/2 > 360 min), and demonstrates IC50s greater than 20 μM for the CYP isoforms tested (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4)^[1].

Assay

Methods	Test Index	PMID
Western blot	p-AKT / AKT / p-p65 / p65 ; PubMed: 27642729 Nature Immunoblotting to detect pThr308Akt, total Akt, phospho-p65 and total p65 in LPS and IL-4 stimulated, macrophages that were treated with vehicle or the PI3Kγ inhibitor IPI-549.	27642729

In vivo

In vivo (mice, rats, dog, and monkeys), IPI-549 has excellent oral bioavailability, low clearance, and distributes into tissues with a mean volume of distribution of 1.2 L/kg. It has a favorable pharmacokinetic profile to allow potent and selective inhibition of PI3K-γ in vivo. IPI-549 can significantly reduce neutrophil migration in a dose-dependent manner in mouse model when administered orally at all of the tested doses. In addition, IPI-54 has been shown to inhibit tumor growth in murine syngeneic models through alteration of immune cells in the tumor microenvironment^[1].

Protocol

Cell Research:

^[1]

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Cell lines: SKOV-3 cells
Concentrations: --
Incubation Time: 30 min
Method:
SKOV-3 cells are seeded into 96-well cell culture-grade plates at a density of 200,000 cells/200 μL/well of RPMI-1640 with 10% FBS. Cells are incubated overnight at 5% CO2 and 37 °C. Compounds are added to the cells, resulting in a final DMSO concentration of 0.5%, and incubated for 30 minutes at 5% CO2 and 37 °C. Media is then aspirated and 50 μL/well of ice-cold lysis buffer is added. Plates are incubated on ice for 5 minutes and then centrifuged at 3000 rpm at 4 °C for 5 minutes.

(Only for Reference)

Animal Research:

^[1]

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Animal Models: CD-1 mice, Sprague-Dawley rats, beagle dogs and cynomolgus monkeys.
Dosages: 0.5-1.25 mg/mL(For PO dosing); 5-10 mg/mL(for efficacy studies); 0.25-0.4 mg/mL(for IV dosing)
Administration: p.o.; i.v.
(Only for Reference)

References

[1] Evans CA, et al. ACS Med Chem Lett. 2016, 7(9):862-7.

Solubility (25°C)

In vitro	DMSO	100 mg/mL (189.19 mM)
	Water	Insoluble
	Ethanol	'8 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information Download Eganelisib (IPI-549) SDF

Molecular Weight	528.56
Formula	C₃₀H₂₄N₈O₂
CAS No.	1693758-51-8
Storage	3 years-20°C powder 2 years-80°C in solvent
Synonyms	N/A
Smiles	CC(C1=CC2=C(C(=CC=C2)C#CC3=CN(N=C3)C)C(=O)N1C4=CC=CC=C4)NC(=O)C5=C6N=CC=CN6N=C5N

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Method for preparing DMSO master liquid: ： mg drug pre-dissolved in μL DMSO (Master liquid concentration mg/mL， Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation：Take DMSO master liquid, next addμL PEG300， mix and clarify, next addμL Tween 80，mix and clarify, next add μL ddH₂O，mix and clarify.

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Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2020-09-01)

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT03980041	Recruiting	Drug: IPI-549\|Drug: Nivolumab\|Drug: Placebos	Bladder Cancer\|Urothelial Carcinoma\|Solid Tumor\|Advanced Cancer	Infinity Pharmaceuticals Inc.\|Bristol-Myers Squibb	September 25 2019	Phase 2
NCT02637531	Active not recruiting	Drug: IPI-549\|Drug: Nivolumab	Advanced Solid Tumors (Part A/B/C/D)\|Non-small Cell Lung Cancer (Part E)\|Melanoma (Part E)\|Squamous Cell Cancer of the Head and Neck (Part E)\|Triple Negative Breast Cancer (Part F)\|Adrenocortical Carcinoma (Part G)\|Mesothelioma (Part G)\|High-circulating Myeloid-derived Suppressor Cells (Part H)	Infinity Pharmaceuticals Inc.	December 2015	Phase 1

Tech Support

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Eganelisib (IPI-549)