Discovery of Potent and Selective PI3Kδ Inhibitors for the Treatment of Acute Myeloid Leukemia.

PI3Kδ is an essential target correlated to the occurrence and development of acute myeloid leukemia (AML). Herein, we investigated the pyrazolo[3,4- d ]pyrimidine derivatives as potent and selective PI3Kδ inhibitors with high therapeutic efficacy toward AML. There were 44 compounds designed and prepared in a four-round optimization, and the biological evaluation showed that ( S )-36 exhibited potent PI3Kδ inhibitory activity, high selectivity, and high antiproliferative activities against MV-4-11 and MOLM-13 cells, coupled with high oral bioavailability ( F = 59.6%). In the MOLM-13 subcutaneous xenograft model, ( S )-36 could significantly suppress the tumor progression with a TGI of 67.81% at an oral administration dosage of 10 mg/kg without exhibiting obvious toxicity. Mechanistically, ( S )-36 could robustly inhibit the PI3K/AKT pathway for significant suppression of cell proliferation and remarkable induction of apoptosis both in vitro and in vivo . Thus, compound ( S )-36 represents a promising PI3Kδ inhibitor for the treatment of acute myeloid leukemia with high efficacy.