Small targeted cytotoxics from DNA-encoded chemical libraries

•Conventional chemotherapeutics are associated with undesired toxicities to healthy organs.•Targeted delivery of cytotoxic agents promises to localize drugs where needed.•High affinity low-molecular weight ligands could outperform antibodies in pharmacodelivery applications.•DNA-encoded chemical libraries are a breakthrough tool to identify high-affinity small-molecule ligands for next-generation targeted therapeutics.

Conventional chemotherapeutic drugs do not selectively localize to tumors, causing undesired toxicities to healthy organs, and precluding the escalation to therapeutically active regimens. The selective delivery at sites of disease of potent effector molecules represents a promising strategy for the treatment of cancer and other diseases. High affinity antibodies towards disease-associated antigens are currently the vehicles of choice for the targeted delivery of payloads. Low molecular weight ligands have the potential to overcome some of the intrinsic limitations associated with antibodies, and have recently been proposed for the development of a novel class of targeted therapeutics. However, the identification of binding molecules, which display high affinity properties and exquisite specificity against protein of therapeutic interest, remains a great challenge. DNA-encoded chemical library technology relies on small molecule libraries of unprecedented size to identify high affinity ligands towards specific target proteins, and could help in the development of next generation targeted cytotoxics.