A Small‐Molecule Drug Conjugate for the Treatment of Carbonic Anhydrase IX Expressing Tumors

作者：Nikolaus Krall, Francesca Pretto, Willy Decurtins, Gonçalo J. L. Bernardes, Claudiu T. Supuran, Dario Neri · 发表于：Angewandte Chemie International Edition · 年份：2014 · DOI：10.1002/anie.201310709 · 被引用次数：294 · 研究领域：Enzyme function and inhibition、Biochemical and Molecular Research、Synthesis and Catalytic Reactions

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.