Linperlisib (YY20394; PI3Kδ-IN-2)is a novel, potent, orally bioavailable, and highly selective PI3Kδ inhibitor that was being investigated in a phase I trial for patients with relapse or refractory B-cell malignancies. In vitro and in vivo growth inhibition of PI3K-expressing human tumor cells was achieved with the development of YY-20394. In immune-competent mice with 4T1 and CT26 tumors, YY-20394 also significantly reduced lung metastasis of 4T1 tumors with dose-dependent inhibition. T cells acted as a major mediator for YY-20394's anti-tumor effectiveness. More significantly, YY-20394 achieved long-term immune memory that is specific for CT26 tumors but not for unrelated A20 tumors, and it synergistically improved the anti-tumor efficacy of anti-PD-L1 antibody in the CT26 model. In vitro mechanistic studies revealed that YY-20394 significantly reduced T cell differentiation into Treg in both mouse splenocytes and primary CD4+ T cells from humans. It was also particularly effective at reducing their in vitro IL-10 secretion. Analysis of tumors treated with YY-20394 revealed that the drug reduced IL-10 secretion as well as the proportion of Treg in the leukocytes infiltrating the tumor. Additionally, it had some effects on the tumors' myeloid populations. These findings imply that the novel PI3Kδ inhibitor YY-20394 is a promising and secure immune modulator with significant promise as a cancer immunotherapeutic.

Physicochemical Properties

Molecular Formula	C28H37FN6O5S
Molecular Weight	588.6940
Exact Mass	588.253
Elemental Analysis	C, 57.13; H, 6.34; F, 3.23; N, 14.28; O, 13.59; S, 5.45
CAS #	1702816-75-8
Related CAS #	1702816-75-8;Unknown (HCl);
PubChem CID	91754520
Appearance	Light yellow to yellow solid powder
LogP	2.1
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	12
Rotatable Bond Count	8
Heavy Atom Count	41
Complexity	958
Defined Atom Stereocenter Count	0
InChi Key	NVWKNQGHVMMAJW-UHFFFAOYSA-N
InChi Code	InChI=1S/C28H37FN6O5S/c1-28(2,36)20-5-7-34(8-6-20)17-19-13-21(29)15-22-24(31-27(32-25(19)22)35-9-11-40-12-10-35)18-14-23(33-41(4,37)38)26(39-3)30-16-18/h13-16,20,33,36H,5-12,17H2,1-4H3
Chemical Name	N-[5-[6-fluoro-8-[[4-(2-hydroxypropan-2-yl)piperidin-1-yl]methyl]-2-morpholin-4-ylquinazolin-4-yl]-2-methoxypyridin-3-yl]methanesulfonamide
Synonyms	PI3Kδ-IN-2; Linperlisib; YY20394; YY 20394; YY-20394
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	PI3Kδ (IC50 = 6.4 nM)
ln Vitro	Linperlisib (YY-20394) is under the study for follicular lymphoma that is recurrent and/or resistant.
References	[1]. A novel PI3K inhibitor suppresses tumor progression by immune modulation
Additional Infomation	Linperlisib is an orally available selective inhibitor of the delta form of phosphatidylinositol 3-kinase (PI3-kinase subunit delta; PI3K-delta; PI3Kdelta), with potential antineoplastic activity. Upon oral administration linperlisib selectively binds to and inhibits PI3K-delta and prevents the activation of the PI3K/AKT signaling pathway. This decreases proliferation of and induces cell death in PI3K-delta over-expressing tumor cells. PI3K-delta also plays a key role in the B-cell receptor (BCR) signaling pathway and the proliferation of certain hematologic cancer cells. The targeted inhibition of PI3K-delta is designed to preserve PI3K signaling in normal, non-neoplastic cells, thereby minimizing serious side effects.

Solubility Data

Solubility (In Vitro)

DMSO: ~100 mg/mL (~169.9 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.25 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 25.0 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 2: ≥ 2.5 mg/mL (4.25 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 3: ≥ 2.5 mg/mL (4.25 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.6987 mL	8.4934 mL	16.9869 mL
	5 mM	0.3397 mL	1.6987 mL	3.3974 mL
	10 mM	0.1699 mL	0.8493 mL	1.6987 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.