The Design and Synthesis of Small-Molecule Anticancer Agents Targeted Through Antibody-Drug Conjugates
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A relatively recent addition to the arsenal of potential treatments for cancer involves the use of vascular disrupting agents (VDAs). Small-molecule VDAs target the blood supply of a tumor, starving it of nutrients and oxygen, leading to central tumor necrosis. The Pinney Group (Baylor University) has recently synthesized a variety of unique anticancer agents that function with dual modality; as potent VDAs, and as profoundly cytotoxic anti-proliferative agents. Like many cancer treatments, at a sufficiently high concentration VDAs affect healthy cells as well as malignant cells. In an effort to efficiently target these agents, such as KGP18, towards tumors and the tumor microenvironment, they are being incorporated as payloads into appropriate antibody-drug conjugates (ADCs). These constructs feature a short amino acid sequence for further selectivity along with a self-immolative spacer. The design and synthesis of these linker constructs are presented here. Future studies will determine the efficacy of these ADCs.