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

• Published in: Journal of medicinal chemistry Vol. 67; no. 8; pp. 6638 - 6657
• Main Authors: Tang, Yongmei, Zheng, Yanan, Hu, Xueping, Zhao, Huajun, Cui, Sunliang
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.04.2024; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Class I Phosphatidylinositol 3-Kinases - metabolism; Drug Discovery; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Life Sciences & Biomedicine; Male; Mice; Mice, Nude; Molecular Docking Simulation; Pharmacology & Pharmacy; Phosphoinositide-3 Kinase Inhibitors - chemical synthesis; Phosphoinositide-3 Kinase Inhibitors - chemistry; Phosphoinositide-3 Kinase Inhibitors - pharmacokinetics; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Phosphoinositide-3 Kinase Inhibitors - therapeutic use; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Science & Technology; Structure-Activity Relationship; Xenograft Model Antitumor Assays; P110-DELTA ISOFORM; CELL-PROLIFERATION; PI3K; EFFICACY; IDELALISIB
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00094

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.