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Tumor Targeting with Small Molecule-Drug Conjugates (SMDCs) - Can They be Better than ADCs?

Over the last three decades, anticancer drug discovery and development have undergone a profound shift in focus from classical chemotherapeutics to targeted agents with significantly enhanced potential for tumor specificity and improved side effect profiles. This has included, e.g. small molecules or protein therapeutics acting on different aspects of derailed signaling pathways in cancer cells or, more recently, interfering with deregulated epigenetic modulators. Alternatively, strategies have been developed by which highly potent cytotoxic agents are rendered (more) tumor-specific bymeans of an appended targeting moiety that interactswith a protein unique to or at least significantly more abundant on tumor cell surfaces than on normal cells. Currently, the most important and successful targeting moieties in use are monoclonal antibodies;[1] four antibody-drug conjugates (ADCs) have received marketing authorization for different types of cancers and many more are in clinical development.[2,3] For the vast majority ofADCs, binding to a cell surface receptor results in internalization of the construct and subsequent intracellular drug release by different mechanisms. However, it has been shown that ADCs binding to a non-internalizing target can also exert very potent antitumor activity in animalmodels.[4]Althoughmonoclonal antibodies exhibit exquisite specificity for their protein targets, ADCs, quite intriguingly, are not free of side effects. While the reasons for this observation have not been fully elucidated, one principle issueassociatedwithallprotein-basedcancer therapeutics is their limited ability to extravasate and penetrate deep into a solid tumor mass.[5] In addition, the long circulatory half-life of ADCs may lead to toxicity due to continuous premature drug cleavage. Compared to ADCs, constructs that rely on small molecules, rather than proteins, as tumor-targeting moieties should penetrate solid tumors much more efficiently. In fact, small molecule-drug conjugates (SMDCs) have been explored extensively as potential anticancer agents;[6,7] however, while several SMDCs have been and are also currently evaluated in clinical trials, no SMDC has yet gained marketing approval. Among the limited number of targets that have been addressed by SMDCs so far, the most prominent is the folate receptor. A vinblastine–folate conjugate (vintafolide) has been advanced to phase III clinical trials,[6] but these trials have been terminated for undisclosed reasons. Recently, the group of Dario Neri at the ETH Zürich has described the SMDC AAZ-MMAE[8] (Fig. 1) that is derived from the known carbonic anhydrase IX (CAIX) inhibitor acetazolamide