IPI 145

Description

Duvelisib (1201438-56-3) is a potent and selective (IC50’s: PI3Kα = 1602nM, PI3Kβ = 85nM, PI3Kδ= 2.5nM, PI3Kγ = 27nM) dual PI3Kδ/γ inhibitor.1 It inhibits B and T cell proliferation, blocks neutrophil migration, and inhibits basophil activation. Duvelisib antagonizes B-cell receptor cross-linking activated pro-survival signals in primary chronic lymphocytic leukemia cells.2?Duvelisib also shows preclinical/clinical activity against other hematologic malignancies such as Non-Hodgkins lymphoma, T-cell lymphoma, and others.3,4?Useful clinical agent for the treatment of various blood cancers. Low-dose treatment of T-cell-inflamed tumor models of head and neck cancers with Duvelisib enhanced responses to PD-L1 blockade via suppression of myeloid-derived suppressor cells.5?Higher doses reversed the effect due to suppression of tumor-infiltrating T lymphocytes

Uses

IPI 145 is an 1,2-dihydroisoquinolin-1(2H)-one derivative and has been developed as a modulator of PI3 kinase.

Definition

ChEBI: 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone is a member of isoquinolines.

brand name

Copiktra

General Description

Class: lipid kinase; Treatment: CLL, SLL, FL; Other name: INK1197, IPI145; Oral bioavailability = 42%; Elimination half-life = 4.7 h; Protein binding = 98%

Pharmacokinetics

The recommended dose of duvelisib is 25 mg twice daily, much lower than that of idelalisib (150 mg, bid). Duvelisib is rapidly absorbed, with a peak concentration after 1–2 h. Following the administration of 25 mg of duvelisib, the absolute bioavailability in healthy volunteers is 42%. It is eliminated with a short half-life of 4.7 h, thus requiring twice daily administration.

target

PI3Kγ/δ

IC 50

Metabolism

Duvelisib is primarily metabolized by CYP3A4 to give a monooxidation product, IPI-656, which has no pharmacologically relevant activity.

References

1) Winkler?et al.?(2013),?PI3K-δ and PI3K-γ Inhibition by IPI-145 Abrogates Immune Response and Suppresses Activity in Autoimmune and Inflammatory Disease Models;?Chem. Biol.?20?1309 2) Dong?et al.?(2014),?IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells;?Blood?124?3583 3) Flinn?et al.?(2018),?Duvelisib, a novel dual inhibitor of PI3K-δ/γ, is clinically active in advances hematologic malignancies;?Blood?131?877 4) Faia?et al.?(2018),?The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib, shows preclinical synergy with multiple targeted therapies in hematologic malignancies;?PLoS One?13?e0200725 5) Davis?et al.?(2017),?Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kδ/γ;?Cancer Res.?77?2607