9ray

Crystal structure of human carbonic anhydrase I in complex with N-benzyl-2-(2-chloro-N-(3-chloro-4-methoxyphenyl)acetamido)-2-(4-sulfamoylphenyl)acetamide

spinqualitylabelsall models 9ray, resolution 1.31Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9ray is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.31Å Ligands: A1JD1, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CAH2_HUMAN Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation. Function CAH2_HUMAN Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye. Publication Abstract from PubMed In this study, we explored a dual-target strategy combining the inhibition of human carbonic anhydrase IX (hCA IX), a tumor-associated isoform, and glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. We demonstrated that the simultaneous inhibition of hCA IX and GPX4 disrupts redox and iron homeostasis, thereby enhancing cell death via ferroptosis. Three series of compounds were rationally designed and synthesized based on the ML162 scaffold using an integrated structural approach and their enzymatic inhibition was evaluated in vitro. Several dual-target compounds exhibited significant antitumor activity, with 18a-c, 22abab and 22abcb inducing dose-dependent cell death. In vivo, intratumoral administration of the lead active compound, 22abcb, significantly prevented the growth of CA IX-expressing human breast cancer xenografts, compared to inactive 22abbb. The effect on tumour growth was significantly reversed by the ferroptosis inhibitor, Fer-1, confirming ferroptosis as the underlying mechanism. These findings highlight the synergistic potential of dual-target inhibitors in disrupting tumor-specific metabolic pathways and position them as a promising therapeutic strategy for solid tumors. Dual inhibition of carbonic anhydrase IX and glutathione peroxidase 4 as a novel strategy for ferroptosis-induced tumor cell death.,Renzi G, McDonald PC, Awrey S, Tavakoli H, Bokhari Z, Lyle M, Zhang Z, Ferraroni M, Dedhar S, Supuran CT, Angeli A Eur J Med Chem. 2025 Dec 15;300:118107. doi: 10.1016/j.ejmech.2025.118107. Epub , 2025 Sep 2. PMID:40929808 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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