Carbonic Anhydrase XII Inhibitors Overcome Temozolomide Resistance in Glioblastoma.
Basic Information
ID: ALA4334437
Journal: J Med Chem
Title: Carbonic Anhydrase XII Inhibitors Overcome Temozolomide Resistance in Glioblastoma.
Authors: Mujumdar P, Kopecka J, Bua S, Supuran CT, Riganti C, Poulsen SA.
Abstract: The natural product primary sulfonamide, psammaplin C (1), when used in combination with clinically used chemotherapeutic drugs, including temozolomide, reverses multidrug resistance and increases survival in glioblastoma, a highly aggressive primary brain tumor. We showed previously that the mechanism of action of 1 is novel, acting to indirectly interfere with P-glycoprotein drug efflux activity as a consequence of carbonic anhydrase XII (CA XII) inhibition. To build structure-activity relationships, 45 derivatives of 1 were designed, synthesized, and evaluated against a panel of CA isoforms. Compound 55 was identified as a potent inhibitor of CA XII ( Ki = 0.56 nM) and was investigated in vitro and in vivo using samples from glioblastoma patients. The results strengthen the possibility that co-therapy of temozolomide with a CA XII inhibitor may more effectively treat glioblastoma by suppressing an important temozolomide resistance mechanism.
CiteXplore: 30925064
DOI: 10.1021/acs.jmedchem.9b00282
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