9p0w
From Proteopedia
Human carbonic anhydrase II in complex with TDP4
Structural highlights
DiseaseCAH2_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.[1] [2] [3] [4] [5] FunctionCAH2_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.[6] [7] Publication Abstract from PubMedCarbonic anhydrases (CAs) have emerged as promising drug targets for cancer therapy. In particular, the human (h) CA IX (hCA IX) isoform is expressed in a wide variety of malignancies and appears tightly regulated by micro-environmental hypoxia. Ongoing efforts aim to identify novel classes of selective CA inhibitors (CAIs) by exploring molecular diversity and discovering original chemotypes and pharmacophores. Previously, we identified a new hit compound (TDP1) carrying a trifluorodihydroxypropanone (TDP) motif as an original zinc-binding function (ZBF), which has undergone structural optimization to generate derivatives with selective inhibition profile toward hCA IX. Herein, we report on the synthesis, biological evaluation, X-ray crystallographic analysis, and computational studies of a series of aromatic-substituted TDP derivatives as novel CAI-directed chemotypes. The most potent compounds selectively inhibited hCA IX, with K(I) values in the submicromolar to high nanomolar range and exhibited significant antiproliferative activity against representative normoxic and hypoxic pancreatic tumor cell lines. Ultrastructural studies indicated for TDPs a possible interference with the mitochondrial function or iron metabolism. Moreover, X-ray crystallography data provided insights into the CA inhibition mechanism, suggesting that these compounds behave similarly to classical CAIs. In summary, this original TDP pharmacophore effectively inhibits human CAs, with relative selectivity towards hCA IX over cytosolic isoforms, thus providing structural insights for the development of a new class of selective anticancer agents. Design, anticancer activity, and mechanistic evaluation of a novel class of selective human carbonic anhydrase IX inhibitors featuring a trifluorodihydroxypropanone pharmacophore.,Pala N, Ladu F, Szlasa W, Cadoni R, Lomelino C, Mahon BP, Gulkis M, McKenna R, Dessi A, Dallocchio R, Demelas A, Carcelli M, Rogolino D, Crosio C, Iaccarino C, Kulbacka J, Vullo D, Carta F, Supuran CT, Sechi M Eur J Med Chem. 2025 Nov 15;298:118043. doi: 10.1016/j.ejmech.2025.118043. Epub , 2025 Aug 5. PMID:40782472[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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