Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2022 Jan;43(1):209-219. doi: 10.1038/s41401-021-00644-1. Epub 2021 Mar 29.
PI3Kδ is expressed predominately in leukocytes and overexpressed in B-cell-related malignances. PI3Kδ has been validated as a promising target for cancer therapy, and specific PI3Kδ inhibitors were approved for clinical practice. However, the substantial toxicity and relatively low efficacy as a monotherapy in diffuse large B-cell lymphoma (DLBCL) limit their clinical use. In this study, we described a novel PI3Kδ inhibitor SAF-248, which exhibited high selectivity for PI3Kδ (IC = 30.6 nM) over other PI3K isoforms at both molecular and cellular levels, while sparing most of the other human protein kinases in the kinome profiling. SAF-248 exhibited superior antiproliferative activity against 27 human lymphoma and leukemia cell lines compared with the approved PI3Kδ inhibitor idelalisib. In particular, SAF-248 potently inhibited the proliferation of a panel of seven DLBCL cell lines (with GI values < 1 μM in 5 DLBCL cell lines). We demonstrated that SAF-248 concentration-dependently blocked PI3K signaling followed by inducing G phase arrest and apoptosis in DLBCL KARPAS-422, Pfeiffer and TMD8 cells. Its activity against the DLBCL cells was negatively correlated to the protein level of PI3Kα. Oral administration of SAF-248 dose-dependently inhibited the growth of xenografts derived from Pfeiffer and TMD8 cells. Activation of mTORC1, MYC and JAK/STAT signaling was observed upon prolonged treatment and co-targeting these pathways would potentiate the activity of SAF-248. Taken together, SAF-248 is a promising selective PI3Kδ inhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy.
PI3Kδ 主要在白细胞中表达，在 B 细胞相关恶性肿瘤中过度表达。PI3Kδ 已被验证为癌症治疗的一个有前途的靶点，并且特定的 PI3Kδ 抑制剂已被批准用于临床实践。然而，在弥漫性大 B 细胞淋巴瘤（DLBCL）中，其作为单一疗法的毒性大、疗效相对较低，限制了其临床应用。在这项研究中，我们描述了一种新型的 PI3Kδ 抑制剂 SAF-248，它在分子和细胞水平上对 PI3Kδ（IC50=30.6 nM）表现出高度的选择性，而在激酶组分析中对大多数其他人类蛋白激酶则具有较高的选择性。与已批准的 PI3Kδ 抑制剂idelalisib 相比，SAF-248 对 27 个人淋巴瘤和白血病细胞系表现出优越的抗增殖活性。特别是，SAF-248 能有效抑制七种 DLBCL 细胞系（在 5 种 DLBCL 细胞系中 GI 值<1 μM）的增殖。我们证明 SAF-248 浓度依赖性地阻断 PI3K 信号通路，随后诱导 DLBCL KARPAS-422、Pfeiffer 和 TMD8 细胞的 G1 期阻滞和凋亡。其对 DLBCL 细胞的活性与 PI3Kα 蛋白水平呈负相关。口服 SAF-248 剂量依赖性地抑制 Pfeiffer 和 TMD8 细胞来源的异种移植物的生长。在延长治疗过程中观察到 mTORC1、MYC 和 JAK/STAT 信号通路的激活，共同靶向这些通路将增强 SAF-248 的活性。总之，SAF-248 是一种有前途的用于治疗 DLBCL 的选择性 PI3Kδ 抑制剂，合理的药物联合治疗将进一步提高其疗效。
