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.

中文翻译：

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发现治疗急性髓系白血病的强效选择性 PI3Kδ 抑制剂

PI3Kδ是与急性髓系白血病（AML）发生、发展相关的重要靶点。在此，我们研究了吡唑并[3,4- d ]嘧啶衍生物作为有效且选择性的PI3Kδ抑制剂，对AML具有较高的治疗效果。经过四轮优化设计制备了44个化合物，生物学评价表明( S )-36对MV-4-11和MOLM-13细胞表现出强效的PI3Kδ抑制活性、高选择性和高抗增殖活性。加上高口服生物利用度（F = 59.6%）。在MOLM-13皮下异种移植模型中，( S )-36口服剂量10 mg/kg即可显着抑制肿瘤进展，TGI为67.81%，且无明显毒性。从机制上讲，( S )-36可以强力抑制 PI3K/AKT 通路，从而在体外和体内显着抑制细胞增殖并显着诱导细胞凋亡。因此，化合物( S )-36代表了一种有前途的PI3Kδ抑制剂，用于高效治疗急性髓系白血病。