A small-molecule drug conjugate for the treatment of carbonic anhydrase IX expressing tumors

Antibody-drug conjugates are a very promising class of new anticancer agents, but the use of small-molecule ligands for the targeted delivery of cytotoxic drugs into solid tumors is less well established. Here, we describe the first small-molecule drug conjugates for the treatment of carbonic anhydrase IX expressing solid tumors. Using ligand-dye conjugates we demonstrate that such molecules can preferentially accumulate inside antigen-positive lesions, have fast targeting kinetics and good tumor-penetrating properties, and are easily accessible by total synthesis. A disulfide-linked drug conjugate with the maytansinoid DM1 as the cytotoxic payload and a derivative of acetazolamide as the targeting ligand exhibited a potent antitumor effect in SKRC52 renal cell carcinoma in vivo. It was furthermore superior to sunitinib and sorafenib, both small-molecule standard-of-care drugs for the treatment of kidney cancer. Size advantage: Antibodies are currently the most widely used vehicles for drug-delivery applications. Small-molecule ligands, however, may have improved pharmacokinetics and better tissue penetration. Targeted small-molecule drug conjugates directed against the tumor marker carbonic anhydrase IX were synthesized, characterized in vitro, and tested in vivo. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim