Open AccessPuquitinib, a novel orally available PI 3Kδ inhibitor, exhibits potent antitumor efficacy against acute myeloid leukemia
Author(s) -
Xie Chengying,
He Ye,
Zhen Mingyue,
Wang Yulan,
Xu Yongping,
Lou Liguang
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13263
Subject(s) - myeloid leukemia , daunorubicin , pharmacology , pi , apoptosis , downregulation and upregulation , cell growth , protein kinase b , kinase , mapk/erk pathway , chemistry , cancer research , leukemia , ic50 , biology , immunology , in vitro , biochemistry , gene
The PI 3Kδ isoform ( PIK 3 CD ), also known as P110δ, is predominately expressed in leukocytes and has been implicated as a potential target in the treatment of hematological malignancies. In this report, we detailed the pharmacologic properties of puquitinib, a novel, orally available PI 3Kδ inhibitor. Puquitinib, which binds to the ATP ‐binding pocket of PI 3Kδ, was highly selective and potent for PI 3Kδ relative to other PI 3K isoforms and a panel of protein kinases, exhibiting low‐nanomolar biochemical and cellular inhibitory potencies. Additional cellular profiling demonstrated that puquitinib inhibited proliferation, induced G 1 ‐phase cell‐cycle arrest and apoptosis in acute myeloid leukemia ( AML ) cell lines, through downregulation of PI 3K signaling. In in vivo AML xenografts, puquitinib alone showed stronger efficacy than the well‐known p110δ inhibitor, CAL ‐101, in association with a reduction in AKT and ERK phosphorylation in tumor tissues, without causing noticeable toxicity. Furthermore, the combination of puquitinib with cytotoxic drugs, especially daunorubicin, yielded significantly stronger antitumor efficacy compared with each agent alone. Thus, puquitinib is a promising agent with pharmacologic properties that are favorable for the treatment of AML .