基于吲哚骨架生物电子等排体替换开发新型PI3Kδ抑制剂FD223用于治疗急性髓系白血病

Abstract

Based on indole scaffold, a potent and selective phosphoinositide 3-kinase delta (PI3K δ ) inhibitor, namely FD223 , was developed by the bioisosteric replacement drug discovery approach and studied for the treatment of acute myeloid leukemia (AML). In vitro studies revealed that FD223 displays high potency (IC 50  = 1 nM) and selectivity (29–51 fold over other PI3K isoforms) against PI3K δ , and exhibits efficient inhibition of the proliferation of AML cell lines (MOLM-16, HL-60, EOL-1 and KG-1) by suppressing p-AKT Ser473 thus causing G1 phase arrest during the cell cycle. Further given the favorable pharmacokinetic (PK) profiles of FD223 , in vivo studies were evaluated using xenograft model in nude mice , confirming its significant antitumor efficacy meanwhile with no observable toxicity. All these results are comparable to the positive group of Idelalisib (CAL-101), indicating that FD223 has potential for further development as a promising PI3K δ inhibitor for the treatment of leukemia such as AML.