Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor
Abstract Phosphoinositide 3‐kinases, delta (PI3Kδ) and gamma (PI3Kγ) are enriched in immune cells and regulate the development and function of innate and adaptive immunity. Dual PI3Kδγ inhibitors are considered high value targets for their potential to treat a variety of immune‐mediated diseases, bu...
Main Authors: | , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Wiley
2020-02-01
|
Series: | Pharmacology Research & Perspectives |
Subjects: | |
Online Access: | https://doi.org/10.1002/prp2.559 |
id |
doaj-d35f0a94d6e5495fbd5b168fdf381dbd |
---|---|
record_format |
Article |
spelling |
doaj-d35f0a94d6e5495fbd5b168fdf381dbd2021-05-02T16:27:50ZengWileyPharmacology Research & Perspectives2052-17072020-02-0181n/an/a10.1002/prp2.559Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitorYu Cai0Jun Yu1Ping Ren2Jianlin He3Zhipeng Wu4Kun Xiao5Hong Jia6Jian Wang7Yang Sai8Guangxiu Dai9Xiong Li10Weiguo Su11Karen Ngo12Glenda Castro13Paul D. Acton14Wai‐Ping Fung‐Leung15James P. Edwards16Jennifer Venable17Tadimeti S. Rao18Hutchison MediPharma, Research and Development Center Pudong Shanghai ChinaHutchison MediPharma, Research and Development Center Pudong Shanghai ChinaHutchison MediPharma, Research and Development Center Pudong Shanghai ChinaHutchison MediPharma, Research and Development Center Pudong Shanghai ChinaHutchison MediPharma, Research and Development Center Pudong Shanghai ChinaHutchison MediPharma, Research and Development Center Pudong Shanghai ChinaHutchison MediPharma, Research and Development Center Pudong Shanghai ChinaHutchison MediPharma, Research and Development Center Pudong Shanghai ChinaHutchison MediPharma, Research and Development Center Pudong Shanghai ChinaHutchison MediPharma, Research and Development Center Pudong Shanghai ChinaHutchison MediPharma, Research and Development Center Pudong Shanghai ChinaHutchison MediPharma, Research and Development Center Pudong Shanghai ChinaJanssen Pharmaceutical R&D, LLC. San Diego CA USAJanssen Pharmaceutical R&D, LLC. San Diego CA USAJanssen Pharmaceutical R&D, LLC. Spring House PA USAJanssen Pharmaceutical R&D, LLC. San Diego CA USAJanssen Pharmaceutical R&D, LLC. Spring House PA USAJanssen Pharmaceutical R&D, LLC. San Diego CA USAJanssen Pharmaceutical R&D, LLC. San Diego CA USAAbstract Phosphoinositide 3‐kinases, delta (PI3Kδ) and gamma (PI3Kγ) are enriched in immune cells and regulate the development and function of innate and adaptive immunity. Dual PI3Kδγ inhibitors are considered high value targets for their potential to treat a variety of immune‐mediated diseases, but their discovery has been challenging. Here we describe the preclinical pharmacology of HM5023507, an orally active dual inhibitor of δγ isoforms in immune signaling. HM5023507 inhibited PI3Kδ and PI3Kγ isoforms with greater than 100‐fold selectivity against PI3Kα and PI3Kβ in recombinant enzymatic assays and in primary human immune cells with an exquisite selectivity against other targets. HM5023507 attenuated the PI3Kδ/γ signaling in human basophils (IC50: 42/340 nmol/L; selectivity ratio ~1:8). HM5023507 attenuated the activation and function of human B and T cells, Th17 differentiation of CD4 T cells in the blood of healthy donors and rheumatoid arthritis patients, and cytokine and IgG production in human T and B cell cocultures, in vitro. Orally dosed HM5023507 attenuated PI3K δ/γ‐mediated immune signaling in the rat in a dose‐related manner. In addition, HM5023507 inhibited semiestablished collagen‐induced arthritic inflammation in the rats (ED50 of 0.25mg/kg, p.o. BID or 0.5 mg/kg, QD, AUC: 1422 ng/mL*h), improved histopathology‐ and micro‐computed tomography (µCT)‐based indices of joint damage, bone destruction, and attenuated the levels of anti‐collagen antibody, with an overall anti‐inflammatory profile matching that of a TNFα neutralizing antibody. The PI3K δγ inhibitory profile of HM5023507 and its selectivity make it a useful tool to further delineate immunobiology of dual PI3K δγ targeting.https://doi.org/10.1002/prp2.559collagen‐induced arthritisHM5023507PI3Kδ/γ dual inhibitor |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yu Cai Jun Yu Ping Ren Jianlin He Zhipeng Wu Kun Xiao Hong Jia Jian Wang Yang Sai Guangxiu Dai Xiong Li Weiguo Su Karen Ngo Glenda Castro Paul D. Acton Wai‐Ping Fung‐Leung James P. Edwards Jennifer Venable Tadimeti S. Rao |
spellingShingle |
Yu Cai Jun Yu Ping Ren Jianlin He Zhipeng Wu Kun Xiao Hong Jia Jian Wang Yang Sai Guangxiu Dai Xiong Li Weiguo Su Karen Ngo Glenda Castro Paul D. Acton Wai‐Ping Fung‐Leung James P. Edwards Jennifer Venable Tadimeti S. Rao Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor Pharmacology Research & Perspectives collagen‐induced arthritis HM5023507 PI3Kδ/γ dual inhibitor |
author_facet |
Yu Cai Jun Yu Ping Ren Jianlin He Zhipeng Wu Kun Xiao Hong Jia Jian Wang Yang Sai Guangxiu Dai Xiong Li Weiguo Su Karen Ngo Glenda Castro Paul D. Acton Wai‐Ping Fung‐Leung James P. Edwards Jennifer Venable Tadimeti S. Rao |
author_sort |
Yu Cai |
title |
Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor |
title_short |
Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor |
title_full |
Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor |
title_fullStr |
Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor |
title_full_unstemmed |
Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor |
title_sort |
immunological characterization of hm5023507, an orally active pi3kδ/γ inhibitor |
publisher |
Wiley |
series |
Pharmacology Research & Perspectives |
issn |
2052-1707 |
publishDate |
2020-02-01 |
description |
Abstract Phosphoinositide 3‐kinases, delta (PI3Kδ) and gamma (PI3Kγ) are enriched in immune cells and regulate the development and function of innate and adaptive immunity. Dual PI3Kδγ inhibitors are considered high value targets for their potential to treat a variety of immune‐mediated diseases, but their discovery has been challenging. Here we describe the preclinical pharmacology of HM5023507, an orally active dual inhibitor of δγ isoforms in immune signaling. HM5023507 inhibited PI3Kδ and PI3Kγ isoforms with greater than 100‐fold selectivity against PI3Kα and PI3Kβ in recombinant enzymatic assays and in primary human immune cells with an exquisite selectivity against other targets. HM5023507 attenuated the PI3Kδ/γ signaling in human basophils (IC50: 42/340 nmol/L; selectivity ratio ~1:8). HM5023507 attenuated the activation and function of human B and T cells, Th17 differentiation of CD4 T cells in the blood of healthy donors and rheumatoid arthritis patients, and cytokine and IgG production in human T and B cell cocultures, in vitro. Orally dosed HM5023507 attenuated PI3K δ/γ‐mediated immune signaling in the rat in a dose‐related manner. In addition, HM5023507 inhibited semiestablished collagen‐induced arthritic inflammation in the rats (ED50 of 0.25mg/kg, p.o. BID or 0.5 mg/kg, QD, AUC: 1422 ng/mL*h), improved histopathology‐ and micro‐computed tomography (µCT)‐based indices of joint damage, bone destruction, and attenuated the levels of anti‐collagen antibody, with an overall anti‐inflammatory profile matching that of a TNFα neutralizing antibody. The PI3K δγ inhibitory profile of HM5023507 and its selectivity make it a useful tool to further delineate immunobiology of dual PI3K δγ targeting. |
topic |
collagen‐induced arthritis HM5023507 PI3Kδ/γ dual inhibitor |
url |
https://doi.org/10.1002/prp2.559 |
work_keys_str_mv |
AT yucai immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT junyu immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT pingren immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT jianlinhe immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT zhipengwu immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT kunxiao immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT hongjia immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT jianwang immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT yangsai immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT guangxiudai immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT xiongli immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT weiguosu immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT karenngo immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT glendacastro immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT pauldacton immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT waipingfungleung immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT jamespedwards immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT jennifervenable immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor AT tadimetisrao immunologicalcharacterizationofhm5023507anorallyactivepi3kdginhibitor |
_version_ |
1721489996918030336 |