Conventional cancer therapies rely on the use of drugs, which are not designed or capable of selective accumulation in neoplastic lesions (1). The conjugation to tumor-specific antibodies has been proposed as a strategy to enhance the therapeutic index of potent cytotoxic drugs (2). Despite the clinical therapeutic efficacy shown by ADCs in several different indications and several product approvals, this class of drugs suffers from drawbacks, including a suboptimal penetration of solid neoplastic lesions (3), high cost-of-goods, potential immunogenicity, and recurrent systemic side effects (4). Ligand-based pharmacodelivery strategies based on small molecules such as Small Molecule-Drug Conjugates (SMDCs) and Small Molecule-Radio Conjugates (SMRCs) represent alternative therapeutic modalities in which the mAb is replaced by a small organic ligand with high affinity and exquisite selectivity for a tumor-associated antigen (4) and fused to a cytotoxic drug or to a radionuclide payload. DNA-Encoded Chemical Libraries (DECLs) enable the efficient and cost-effective discovery of novel small organic ligands of cancer targets (5). In this talk, I will present successful applications of DECLs for the discovery of highly potent and selective tumor-targeting ligands against various tumor-associated antigens (6-8). Moreover, I will describe the generation and in vivo characterization of SMDCs and SMRCs based on DECL-derived ligands (9, 10).

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