Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-13-2, Fukuura, Kanazawa-Ku, Yokohama, Kanagawa 236-0004, Japan.
Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-13-2, Fukuura, Kanazawa-Ku, Yokohama, Kanagawa 236-0004, Japan.
Biochem Biophys Res Commun. 2019 Oct 8;518(1):32-37. doi: 10.1016/j.bbrc.2019.08.004. Epub 2019 Aug 6.
JTE-607 is a small molecule that was developed as an inflammatory cytokine inhibitor and also as an anti-leukemia reagent for monocytic leukemia. However, the mode of action of JTE-607 remains unknown. In this study, we identified JTE-607 to be a prodrug compound that is converted to an active form by ester hydrolysis. Furthermore, we determined that the active form of JTE-607 bound cleavage and polyadenylation specificity factor subunit 3 (CPSF3), using compound-immobilized affinity chromatography. CPSF3 is a 73-kDa subunit of the cleavage and polyadenylation specificity factor complex, which functions as an RNA endonuclease. The protein is involved in the 3'-end processing of messenger RNA precursors (pre-mRNAs) at the cleavage site located downstream of the poly(A) addition signal. We found that treatment with JTE-607 caused accumulation of pre-mRNAs. Furthermore, knockdown experiments showed that CPSF3 deficiency also caused accumulation of pre-mRNAs and suppressed the expression of inflammatory cytokines, like JTE-607. These findings indicated that CPSF3 is a direct target of JTE-607 and a new potential target for the treatment of disease-related abnormal cytokine production.
JTE-607 是一种小分子，被开发为炎症细胞因子抑制剂和单核细胞白血病的抗白血病试剂。然而，JTE-607 的作用模式尚不清楚。在这项研究中，我们确定 JTE-607 是一种前药化合物，可通过酯水解转化为活性形式。此外，我们使用固定化化合物亲和层析法确定 JTE-607 的活性形式与切割和多聚腺苷酸化特异性因子亚基 3（CPSF3）结合。CPSF3 是切割和多聚腺苷酸化特异性因子复合物的 73kDa 亚基，作为一种 RNA 内切酶发挥作用。该蛋白参与位于多聚（A）添加信号下游的信使 RNA 前体（pre-mRNAs）在切割位点的 3'末端加工。我们发现 JTE-607 处理会导致 pre-mRNAs 的积累。此外，敲低实验表明 CPSF3 缺陷也会导致 pre-mRNAs 的积累，并抑制炎症细胞因子的表达，就像 JTE-607 一样。这些发现表明 CPSF3 是 JTE-607 的直接靶标，也是治疗与疾病相关的异常细胞因子产生的新的潜在靶标。
