6ic2
Polypharmacology of Epacadostat: a Potent and Selective Inhibitor of the Tumor Associated Carbonic Anhydrases IX and XII
Structural highlights
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.[1] [2] [3] [4] [5] 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.[6] [7] Publication Abstract from PubMedEpacadostat (EPA), a selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, has been investigated in vitro as a human (h) Carbonic Anhydrase Inhibitor (CAI). The kinetic data clearly show, for the first time, EPA to be a highly effective and selective inhibitor for the tumor-associated isoforms hCA IX/XII. We report the high resolution X-ray crystal structure of the EPA-hCA II adduct, and assessed its binding mode to CA IX/XII by means of computational techniques. EPA may exert antitumor effects also due to the potent inhibition of the tumor-associated CAs. Polypharmacology of epacadostat: a potent and selective inhibitor of the tumor associated carbonic anhydrases IX and XII.,Angeli A, Ferraroni M, Nocentini A, Selleri S, Gratteri P, Supuran CT, Carta F Chem Commun (Camb). 2019 May 14;55(40):5720-5723. doi: 10.1039/c8cc09568j. PMID:31038135[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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