Schultz Chad R, Aleiwi Bilal, Zhou X Edward, Suino-Powell Kelly, Melcher Karsten, Almeida Nuno M S, Wilson Angela K, Ellsworth Edmund L, Bachmann André S
Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503, United States.
International Center for Polyamine Disorders, Grand Rapids, Michigan 49503, United States.
J Med Chem. 2025 Mar 13;68(5):5760-5773. doi: 10.1021/acs.jmedchem.4c03120. Epub 2025 Mar 4.
We here describe the design, synthesis, and biological activity of novel ornithine decarboxylase (ODC) inhibitors that show significantly higher potency than α-difluoromethylornithine (DFMO), a U.S. Food and Drug Administration (FDA) approved drug. We report two X-ray structures of ODC complexed with new ODC inhibitors, computational docking, molecular dynamics, and binding free energy calculations to validate the experimental models. The X-ray structures reveal that covalent adducts with pyridoxal phosphate (PLP) are formed in the active site of the human ODC enzyme, as verified by their preparation and enzymatic testing. Finally, we verified that the cellular activity of endogenous ODC was inhibited, and polyamine levels were reduced. Given that ODC is a clinically validated target, combined with the fact that DFMO is currently the only ODC inhibitor in clinical use for several indications, the further development of more potent ODC inhibitors with superior activity and physical properties is warranted.
我们在此描述了新型鸟氨酸脱羧酶（ODC）抑制剂的设计、合成及生物活性，这些抑制剂的效力显著高于美国食品药品监督管理局（FDA）批准的药物α-二氟甲基鸟氨酸（DFMO）。我们报告了ODC与新型ODC抑制剂复合的两个X射线结构、计算对接、分子动力学及结合自由能计算，以验证实验模型。X射线结构显示，在人ODC酶的活性位点形成了与磷酸吡哆醛（PLP）的共价加合物，这通过它们的制备和酶学测试得到了验证。最后，我们证实内源性ODC的细胞活性受到抑制，多胺水平降低。鉴于ODC是一个经过临床验证的靶点，再加上DFMO目前是临床用于多种适应症的唯一ODC抑制剂这一事实，有必要进一步开发具有更优活性和物理性质的更高效ODC抑制剂。
