A Small‐Molecule Drug Conjugate for the Treatment of Carbonic Anhydrase IX Expressing Tumors†
The research conducted by the Neri group on small‐molecule‐based tumor targeting is funded by ETH Zurich, the Swiss National Science Foundation, and Oncosuisse. Prof. Dario Neri is a shareholder of Philochem AG, which has licensed small‐molecule drug‐delivery technology from ETH Zurich. We thank EMBO for a Long‐Term Fellowship to G.J.L.B. and Dr. Raphael Franzini and Dr. Giulio Casi for critically reading the manuscript.
Abstract
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.
