Summary of recent advances
Existing drugs address a relatively narrow range of biological targets. As a result, libraries of drug-like molecules have proven ineffective against a variety of challenging targets, such as protein–protein interactions, nucleic acid complexes, and antibacterial modalities. In contrast, natural products are known to be effective at modulating such targets, and new libraries are being developed based on underrepresented scaffolds and regions of chemical space associated with natural products. This has led to several recent successes in identifying new chemical probes that address these challenging targets.
Monoclonal antibodies have evolved from research tools to powerful therapeutics in the past 30 years. Clinical success rates of antibodies have exceeded expectations, resulting in heavy investment in biologics discovery and development in addition to traditional small molecules across the industry. However, protein therapeutics cannot drug targets intracellularly and are limited to soluble and cell-surface antigens. Tremendous strides have been made in antibody discovery, protein engineering, formulation, and delivery devices. These advances continue to push the boundaries of biologics to enable antibody conjugates to take advantage of the target specificity and long half-life from an antibody, while delivering highly potent small molecule drugs. While the “magic bullet” concept produced the first wave of antibody conjugates, these entities were met with limited clinical success. This review summarizes the advances and challenges in the field to date with emphasis on antibody conjugation, linker-payload chemistry, novel payload classes, absorption, distribution, metabolism, and excretion (ADME), and product developability. We discuss lessons learned in the development of oncology antibody conjugates and look towards future innovations enabling other therapeutic indications.
Acortatarins A and B have been synthesized via stereoselective spirocyclizations of glycals. Mercury-mediated spirocyclization of a pyrrole monoalcohol sidechain leads to acortatarin A. Glycal epoxidation and reductive spirocyclization of a pyrrole dialdehyde sidechain leads to acortatarin B. Acid equilibration and crystallographic analysis indicate that acortatarin B is a contrathermodynamic spiroketal with distinct ring conformations compared to acortatarin A.
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