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.