State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, China.
Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Xianyang 712100, China.
Int J Mol Sci. 2022 Apr 27;23(9):4806. doi: 10.3390/ijms23094806.
Breast cancer seriously endangers women's health worldwide. Protein arginine methyltransferase 5 (PRMT5) is highly expressed in breast cancer and represents a potential druggable target for breast cancer treatment. However, because the currently available clinical PRMT5 inhibitors are relatively limited, there is an urgent need to develop new PRMT5 inhibitors. Our team previously found that the FDA-approved drug tadalafil can act as a PRMT5 inhibitor and enhance the sensitivity of breast cancer patients to doxorubicin treatment. To further improve the binding specificity of tadalafil to PRMT5, we chemically modified tadalafil, and designed three compounds, A, B, and C, based on the PRMT5 protein structure. These three compounds could bind to PRMT5 through different binding modes and inhibit histone arginine methylation. They arrested the proliferation and triggered the apoptosis of breast cancer cells in vitro and also promoted the antitumor effects of the chemotherapy drugs cisplatin, doxorubicin, and olaparib in combination regimens. Among them, compound A possessed the highest potency. Finally, the anti-breast cancer effects of PRMT5 inhibitor A and its ability to enhance chemosensitivity were further verified in a xenograft mouse model. These results indicate that the new PRMT5 inhibitors A, B, and C may be potential candidates for breast cancer treatment.
乳腺癌严重威胁着全世界女性的健康。精氨酸甲基转移酶 5（PRMT5）在乳腺癌中高度表达，是治疗乳腺癌的潜在药物靶点。然而，由于目前可用的临床 PRMT5 抑制剂相对有限，因此迫切需要开发新的 PRMT5 抑制剂。我们的团队之前发现，已获 FDA 批准的药物他达拉非可作为 PRMT5 抑制剂，增强乳腺癌患者对阿霉素治疗的敏感性。为了进一步提高他达拉非与 PRMT5 的结合特异性，我们对他达拉非进行了化学修饰，并根据 PRMT5 蛋白质结构设计了三种化合物，A、B 和 C。这三种化合物可以通过不同的结合模式与 PRMT5 结合，并抑制组蛋白精氨酸甲基化。它们在体外抑制了乳腺癌细胞的增殖并诱导其凋亡，还增强了顺铂、阿霉素和奥拉帕利联合方案中化疗药物的抗肿瘤作用。其中，化合物 A 的活性最高。最后，在异种移植小鼠模型中进一步验证了 PRMT5 抑制剂 A 的抗乳腺癌作用及其增强化疗敏感性的能力。这些结果表明，新型 PRMT5 抑制剂 A、B 和 C 可能是治疗乳腺癌的潜在候选药物。
