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

Angew Chem Int Ed Engl. 2014 Apr 14;53(16):4231-5. doi: 10.1002/anie.201310709. Epub 2014 Mar 12.

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.

Keywords: cancer therapy; carbonic anhydrase IX; drug conjugates; drug delivery; prodrugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbonic Anhydrases / chemistry*
  • Drug Delivery Systems
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / therapy*
  • Mice
  • Molecular Structure
  • Prodrugs

Substances

  • Prodrugs
  • Carbonic Anhydrases