Puquitinib, a novel orally available PI3Kδ inhibitor, exhibits potent antitumor efficacy against acute myeloid leukemia.

Abstract

The PI3Kδ isoform (PIK3CD), 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 PI3Kδ inhibitor. Puquitinib, which binds to the ATP‐binding pocket of PI3Kδ, was highly selective and potent for PI3Kδ relative to other PI3K isoforms and a panel of protein kinases, exhibiting low‐nanomolar biochemical and cellular inhibitory potencies. Additional cellular profiling demonstrated that puquitinib inhibited proliferation, induced G1‐phase cell‐cycle arrest and apoptosis in acute myeloid leukemia (AML) cell lines, through downregulation of PI3K 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.