Multiple myeloma (MM) is an incurable hematological malignancy, for which novel effective therapies are urgently needed. We synthesized a novel phosphoramide compound, DCZ0847, showing a potent anti-myeloma activity both in vitro and in vivo. DCZ0847 showed high cytotoxicity towards primary MM cells but had no effect on normal cells and was well tolerated in vivo. The anti-myeloma activity of DCZ0847 was associated with inhibition of cell proliferation; promotion of cell apoptosis via mitochondrial transmembrane potential collapse and caspase-mediated extrinsic or intrinsic apoptotic pathways; and the induction of G2/M phase arrest via downregulation of CDC25C, CDK1, and cyclin B1. In particular, DCZ0847 induced DNA damage and triggered a DNA-damage response by enhancing the levels of γ-H2A.X, phosphorylated (p)-ATM, p-ATR, p-Chk1, and p-Chk2. Additionally, DCZ0847 was able to overcome the bone marrow stromal cells-induced proliferation of MM cells and blocked JAK2/STAT3 signaling. Importantly, DCZ0847 acted synergistically with bortezomib, with the combination exerting greater cytotoxic effects in vitro and in vivo. Together, our results indicate that DCZ0847, alone or in combination with bortezomib, may represent a potential new therapy for patients with MM.

多发性骨髓瘤（MM）是一种不可治愈的血液系统恶性肿瘤，迫切需要新的有效疗法。我们合成了一种新型的磷酰胺化合物DCZ0847，在体外和体内均显示出有效的抗骨髓瘤活性。DCZ0847对原代MM细胞显示出高细胞毒性，但对正常细胞没有影响，并且在体内具有良好的耐受性。DCZ0847的抗骨髓瘤活性与细胞增殖的抑制有关。通过线粒体跨膜电位崩溃和半胱天冬酶介导的外在或内在凋亡途径促进细胞凋亡；通过下调CDC25C，CDK1和细胞周期蛋白B1诱导G2 / M期阻滞。特别是，DCZ0847通过增强γ-H2A.X，磷酸化（p）-ATM，p-ATR，p-Chk1和p-Chk2的水平来诱导DNA损伤并触发DNA损伤反应。此外，DCZ0847能够克服骨髓基质细胞诱导的MM细胞增殖并阻断JAK2 / STAT3信号传导。重要的是，DCZ0847与硼替佐米协同作用，与组合施加更大的细胞毒性效果的体外和体内。总之，我们的结果表明DCZ0847单独或与硼替佐米联用可能代表MM患者潜在的新疗法。