Novel Chemicals Derived from Tadalafil Exhibit PRMT5 Inhibition and Promising Activities against Breast Cancer.
Novel Chemicals Derived from Tadalafil Exhibit PRMT5 Inhibition and Promising Activities against Breast Cancer.
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DOI：
10.3390/ijms23094806
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发表时间：
2022-04-27
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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乳腺癌严重危害着全世界妇女的健康。蛋白精氨酸甲基转移酶5 （PRMT5）在乳腺癌中高表达，是乳腺癌治疗的潜在药物靶点。然而，由于目前临床可用的PRMT5抑制剂相对有限，迫切需要开发新的PRMT5抑制剂。我们的团队之前发现fda批准的药物他达拉非可以作为PRMT5抑制剂，提高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，并基于PRMT5蛋白结构设计了A、B、C三种化合物。这三种化合物可以通过不同的结合方式与PRMT5结合，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引发了细胞凋亡，同时也促进了化疗药物顺铂、阿霉素和奥拉帕尼联合治疗方案的抗肿瘤作用。其中化合物A的效价最高。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。这些结果表明新的PRMT5抑制剂A、B和C可能是乳腺癌治疗的潜在候选者。
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.
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影响因子：
8.8
作者：
Chiang K;Zielinska AE;Shaaban AM;Sanchez-Bailon MP;Jarrold J;Clarke TL;Zhang J;Francis A;Jones LJ;Smith S;Barbash O;Guccione E;Farnie G;Smalley MJ;Davies CC
通讯作者：
Davies CC
DOI：
10.1007/978-3-319-46503-6_7
发表时间：
2017-01-01
期刊：
MACROMOLECULAR PROTEIN COMPLEXES: STRUCTURE AND FUNCTION
影响因子：
--
作者：
Antonysamy, Stephen
通讯作者：
Antonysamy, Stephen
影响因子：
120.7
作者：
Kuchenbaecker, Karoline B.;Hopper, John L.;Antoniou, Antonis C.
通讯作者：
Antoniou, Antonis C.
影响因子：
5.6
作者：
Fan C;Wang Y;Huang H;Li W;Ma J;Yao D;Tang Z;Xue T;Ha L;Ren Y;Zhang Y;Wang Q;Xie Y;Luo Y;Tan R;Gu J
通讯作者：
Gu J
影响因子：
4.3
作者：
Marquette, Carrie;Nabell, Lisle
通讯作者：
Nabell, Lisle