Duvelisib R enantiomer is the R-isomer of Duvelisib (formerly known as IPI-145 and INK1197, trade name: Copiktra) which is an isoquinolinone derivative and a novel potent, oral and selective small-molecule phosphoinositide-3 kinases (PI3K) inhibitor that selectively and potently inhibits two PI3K isoforms, PI3K-δ and PI3K-γ, with half maximal inhibition concentration IC50 of 2.5 nM and 27 nM respectively. FDA approved duvelisib in September 2018 to treat small lymphocytic lymphoma, follicular lymphoma, and chronic lymphocytic leukemia that has relapsed or is resistant to treatment. Despite having a preference for PI3K-δ and PI3K-γ, IPI-145 also inhibits PI3K-α and PI3K-β to a lesser extent, with IC50 values of 1602 nM and 85 nM, respectively. Phosphoinositide-3-kinase (PI3K) is an enzyme group, known to regulate key survival pathways in acute myeloid leukaemia (AML). It produces phosphatidylinositol-3,4,5-triphosphate, which offers a membrane docking site for protein kinaseB activation. There are four isoforms of the p110 catalytic subunit of PI3K:,, and. In contrast to the highly variable frequency of PI3Kγ expression, the PI3Kδ isoform is consistently expressed in AML cells. The roles of these individual catalytic enzymes have not been fully elucidated in AML, so the function of these two p110 subunits in human AML blast survival was investigated using the PI3K p110δ and p110γ targeted inhibitor IPI-145 (duvelisib) and specific p110δ and p110γ shRNA.

Physicochemical Properties

Molecular Formula	C22H17CLN6O
Molecular Weight	416.86
Exact Mass	416.115
CAS #	1261590-48-0
Related CAS #	Duvelisib;1201438-56-3
PubChem CID	68353646
Appearance	White to gray solid
Density	1.5±0.1 g/cm3
Boiling Point	757.8±60.0 °C at 760 mmHg
Flash Point	412.1±32.9 °C
Vapour Pressure	0.0±2.6 mmHg at 25°C
Index of Refraction	1.757
LogP	4.6
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	4
Heavy Atom Count	30
Complexity	668
Defined Atom Stereocenter Count	1
SMILES	ClC1=C([H])C([H])=C([H])C2=C1C(N(C1C([H])=C([H])C([H])=C([H])C=1[H])C(=C2[H])C([H])(C([H])([H])[H])N([H])C1C2=C(N=C([H])N=1)N=C([H])N2[H])=O
InChi Key	SJVQHLPISAIATJ-CYBMUJFWSA-N
InChi Code	InChI=1S/C22H17ClN6O/c1-13(28-21-19-20(25-11-24-19)26-12-27-21)17-10-14-6-5-9-16(23)18(14)22(30)29(17)15-7-3-2-4-8-15/h2-13H,1H3,(H2,24,25,26,27,28)/t13-/m1/s1
Chemical Name	8-chloro-2-phenyl-3-[(1R)-1-(7H-purin-6-ylamino)ethyl]isoquinolin-1-one
Synonyms	IPI145 R-isomer; IPI 145 R enantiomer; IPI-145. INK1197; INK 1197; INK-1197
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	PI3K
ln Vitro	In Vitro Assay: Duvelisib is a selectivite p100δ inhibitor with IC50 of 2.5 nM, 27.4 nM, 85 nM and 1602 nM for p110δ, P110γ, p110β and p110α, respectively. PI3Kδ and PI3Kγ inhibition with IPI-145 has anti-proliferative activity in primary AML cells by inhibiting the activity of AKT and MAPK. Pre-treatment of AML cells with IPI-145 inhibits both adhesion and migration of AML blasts to bone marrow stromal cells Cell Assay: IPI-145 suppresses murine/human B-cell proliferation with EC50 of 0.5 nM/0.5 nM and also inhibits human T-cell proliferation with EC50 of 9.5 nM.
ln Vivo	IPI-145 (10 mg/kg, p.o.) shows well pharmacokinetics with Cmax and AUC of 390 ng/mL and 137 ng•h/mL in mouse and rat. IPI-145 (10 mg/kg) is active in murine DTH model with ~50% ear swelling. IPI-145 (10 mg/kg) demonstrates dose-dependent effect in rat collagen induced arthritis (CIA) model. IPI-145 prevents inflammation and protects joint bone and cartilage in the rat CIA model. IPI-145 (10 mg/kg,QD) demonstrates activity in rat adjuvant induced polyarthritis model.
Cell Assay	IPI-145 suppresses murine/human B-cell proliferation with EC50 of 0.5 nM/0.5 nM and also inhibits human T-cell proliferation with EC50 of 9.5 nM.
Animal Protocol	10 mg/kg, p.o. Mouse and rat with collagen induced arthritis (CIA) model.
References	[1]. Certain chemical entities, compositions and methods. WO 2011008302 A1.

Solubility Data

Solubility (In Vitro)

DMSO: ~83 mg/mL (!199.1 mM) Water: <1 mg/mL Ethanol: <1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.00 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: ≥ 2.38 mg/mL (5.71 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 23.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 4: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30mg/mL  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.3989 mL	11.9944 mL	23.9889 mL
	5 mM	0.4798 mL	2.3989 mL	4.7978 mL
	10 mM	0.2399 mL	1.1994 mL	2.3989 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.