Inhibition of the BCL6 BTB domain results in killing Diffuse Large B-cell Lymphoma (DLBL) cells, reducing the T-cell dependent germinal center (GC) reaction in mice, and reversing GC hyperplasia in nonhuman primates. The available BCL6 BTB-specific inhibitors are poorly water soluble, thus, limiting their absorption in vivo and our understanding of therapeutic strategy targeting GC. We synthesized a prodrug (AP-4-287) from a potent BCL6 BTB inhibitor (FX1) with improved aqueous solubility and pharmacokinetics (PK) in mice. We also evaluated its in vivo biological activity on humoral immune responses using the sheep red blood cells (SRBC)-vaccination mouse model. AP-4-287 had a significant higher aqueous solubility and was readily converted to FX1 in vivo after intraperitoneally (i.p.) administration, but a shorter half-life in vivo. Importantly, AP-4-287 treatment led to a reversible effect on (1) the reduction in the frequency of splenic Ki67⁺ CD4⁺ T cells, Tfh cells, and GC B cells; (2) lower GC formation following vaccination; and (3) a decrease in the titers of antigen-specific IgG and IgM antibodies. Our study advances the preclinical development of drug targeting BCL6 BTB domain for the treatment of diseases that are associated with abnormal BCL6 elevation.

中文翻译：

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BCL6 BTB 特异性抑制剂在体内反向抑制 T 细胞活化、Tfh 细胞分化和生发中心反应

抑制 BCL6 BTB 结构域可杀死弥漫性大 B 细胞淋巴瘤 (DLBL) 细胞，减少小鼠的 T 细胞依赖性生发中心 (GC) 反应，并逆转非人灵长类动物的 GC 增生。可用的 BCL6 BTB 特异性抑制剂水溶性差，因此限制了它们在体内的吸收和我们对靶向 GC 的治疗策略的理解。我们从一种有效的 BCL6 BTB 抑制剂 (FX1) 合成了一种前药 (AP-4-287)，该抑制剂在小鼠体内具有改善的水溶性和药代动力学 (PK)。我们还使用绵羊红细胞 (SRBC) 疫苗接种小鼠模型评估了其对体液免疫反应的体内生物活性。AP-4-287 具有显着更高的水溶性，并且在腹膜内 (ip) 给药后很容易在体内转化为 FX1，但在体内的半衰期较短。重要的，⁺ CD4 ⁺ T 细胞、Tfh 细胞和 GC B 细胞；(2) 疫苗接种后 GC 形成降低；(3) 抗原特异性 IgG 和 IgM 抗体的滴度降低。我们的研究推进了靶向 BCL6 BTB 结构域的药物的临床前开发，用于治疗与异常 BCL6 升高相关的疾病。