Ilaria D’Agostino, Alessandro Bonardi, Marta Ferraroni, Paola Gratteri, Andrea Angeli* and Claudiu T. Supuran,
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引用次数: 0
摘要
PCI-27483最初是作为丝氨酸蛋白酶因子VIIa（FVIIa）与组织因子（TF）复合物的强效选择性抑制剂而开发的，在癌症治疗中展现出了巨大的前景。除了其主要作用机制外，PCI-27483 结构中磺胺分子的存在还表明它还能通过抑制碳酸酐酶（CAs），特别是与肿瘤相关的人类（h）CA 异构体 hCA IX 和 XII 发挥进一步的作用。本研究调查了 PCI-27483 对全部活性 hCA 的抑制活性，凸显了其在癌症治疗中的多药理潜力。X 射线晶体学和分子对接研究阐明了 PCI-27483 对 hCA IX 和 XII 具有选择性抑制活性的结构特征，为其双靶向途径提供了深入见解。
Exploring the Polypharmacological Potential of PCI-27483: A Selective Inhibitor of Carbonic Anhydrases IX and XII
PCI-27483, originally developed as a potent and selective inhibitor of the serine protease Factor VIIa (FVIIa) in complex with tissue factor (TF), has demonstrated significant promise in cancer therapy. In addition to its primary mechanism of action, the presence of a sulfonamide moiety in the PCI-27483 structure suggests further activities through the inhibition of carbonic anhydrases (CAs), particularly the tumor-associated human (h)CA isoforms hCA IX and XII. This study investigates the inhibitory activity of PCI-27483 against the complete panel of active hCAs, highlighting its polypharmacological potential in cancer treatment. X-ray crystallography and molecular docking studies elucidated the structural features underlying its selective inhibitory activity toward hCA IX and XII, offering insights into its dual-targeting pathway.
期刊介绍：
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.
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