Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Maryland 21702, United States.
J Med Chem. 2024 Oct 24;67(20):17964-17979. doi: 10.1021/acs.jmedchem.4c01566. Epub 2024 Oct 11.
The emerging data compiled during the past five years on 3-deazaneplanocin (DZNep) provide compelling evidence to reevaluate this drug as a better alternative over the specific catalytic inhibitors of histone methyl transferases (HTMs). The indirect mechanism of DZNep via inhibition of AdoHcy-ase, once considered a liability due to possible side effects, has now shown to be rather beneficial as additional pathways targeted by DZNep are important contributors to its superior anticancer properties. Furthermore, DZNep has demonstrated the ability to induce proteasomal degradation of its target and reduce toxicity in combination with well-established antitumor therapies in animal models. In addition, DZNep has shown important effects in suppressing fibrosis and inflammation in liver, kidney, peritoneum, and airways. Finally, inhibition of mRNA mA methylation by DZNep suppresses the synthesis of the viral genome in SARS-Cov-2 infection and promises to have important therapeutic value when combined with its potent antiviral efficacy and anti-inflammatory effects.
在过去五年中积累的新兴数据为 3-去氮杂胞苷（DZNep）提供了令人信服的证据，使其重新成为组蛋白甲基转移酶（HTMs）特异性催化抑制剂的更好替代品。DZNep 通过抑制 AdoHcy-ase 的间接机制，由于可能产生副作用而一度被认为是不利因素，但现在看来这是有益的，因为 DZNep 靶向的其他途径是其卓越抗癌特性的重要贡献者。此外，DZNep 已证明能够诱导靶蛋白的蛋白酶体降解，并在动物模型中与经过验证的抗肿瘤疗法联合使用时降低毒性。此外，DZNep 在抑制肝脏、肾脏、腹膜和气道中的纤维化和炎症方面显示出重要作用。最后，DZNep 抑制 mRNA mA 甲基化可抑制 SARS-CoV-2 感染中的病毒基因组合成，并有望与强大的抗病毒功效和抗炎作用相结合具有重要的治疗价值。
