Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor

Pharmacology Research & Perspectives

Jianlin He¹  Kun Xiao¹  Yang Sai¹  Ping Ren¹  Jun Yu¹  Jian Wang¹  Weiguo Su¹  Xiong Li¹  Yu Cai¹  Hong Jia¹  Guangxiu Dai¹  Zhipeng Wu¹  Karen Ngo²  Jennifer Venable²  Wai‐Ping Fung‐Leung²  Tadimeti S. Rao²  Glenda Castro²  Paul D. Acton³  James P. Edwards³ 

[1] Hutchison MediPharma, Research and Development Center Pudong Shanghai China;Janssen Pharmaceutical R&D, LLC. San Diego CA USA;Janssen Pharmaceutical R&D, LLC. Spring House PA USA;

关键词: collagen‐induced arthritis;    HM5023507;    PI3Kδ/γ dual inhibitor;   

DOI  :  10.1002/prp2.559

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown