Polypharmacology of sulfonamides: pazopanib, a multitargeted receptor tyrosine kinase inhibitor in clinical use, potently inhibits several mammalian carbonic anhydrases.
Pazopanib, a new, multi-targeted tyrosine kinase inhibitor (TKI) used clinically for the treatment of several types of tumors, incorporates a primary sulfonamide moiety normally associated with the inhibition of the metallo enzyme carbonic anhydrase (CA, EC 4.2.1.1). Here we show that pazopanib and related sulfonamides such as indisulam, acetazolamide or ureido-substituted peptidomimetic benzenesulfonamides are low nanomolar inhibitors of many of the fifteen human isoforms hCA I-XIV. These data indicate that in addition to the TK inhibitory action, pazopanib may exert antitumor/antimetastatic effects also due to the potent inhibition of the tumor-associated, hypoxia-inducible enzymes CA IX and XII.
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-UM1-UM2, Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France.
Jean-Yves
JY
Winum
Alfonso
A
Maresca
Fabrizio
F
Carta
Andrea
A
Scozzafava
Claudiu T
CT
Supuran
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism*; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007191:Indazoles; D008958:Models, Molecular; D011743:Pyrimidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D020794:Receptor Protein-Tyrosine Kinases; D002256:Carbonic Anhydrases