A Comprehensive Review of the Antitumor Properties and Mechanistic Insights of Duocarmycin Analogs.

Simple Summary: The duocarmycin family consists of highly potent cytotoxic agents originally derived from the bacterium Streptomyces. This review explores their unique chemical structures, which include a DNA-binding unit, a subunit-linking amide for positioning within the DNA helix, and an alkylating unit that targets adenine bases. Duocarmycins disrupt DNA replication and transcription by forming covalent bonds with DNA. Recent advances, such as the development of antibody–drug conjugates (ADCs), have enhanced the potential for targeting cancer cells more effectively. Although preclinical studies show promise, further research is needed to understand the toxicology of duocarmycins before they can be widely applied in cancer treatment. This review summarizes key findings and suggests next steps for improving duocarmycin-based therapies. The duocarmycin family is a group of potent cytotoxic agents originally isolated from the bacterium Streptomyces. This discovery has spurred significant interest due to duocarmycins' unique chemical structures and powerful mechanism of action. This review comprehensively details the history of the duocarmycin family, the current understanding of their therapeutic potential, and the major clinical trials that have been conducted. Chemically, the duocarmycin family is characterized by a DNA-binding unit that confers specificity, a subunit-linking amide that positions the molecule within the DNA helix, and an alkylating unit that interacts with the DNA. This configuration allows them to bind selectively to the minor groove of DNA and alkylate adenine bases, a notable deviation from the more common guanine targeting performed by other alkylating agents. Duocarmycin's mechanism of action involves the formation of covalent adducts with DNA, leading to the disruption of the DNA architecture and subsequent inhibition of replication and transcription. Recent advancements in drug delivery systems, such as antibody–drug conjugates (ADCs), have further elevated the therapeutic prospects of duocarmycin analogs by providing a promising mechanism for enhancing intracellular concentrations and selective tumor delivery. Preclinical studies have highlighted the efficacy of duocarmycin derivatives in various in vitro models, providing a strong foundation for translational research. However, further biological research is required to fully understand the toxicology of duocarmycin family members before it can be clinically relevant. The major focus of this review is to cache the major biologically relevant findings of different duocarmycin analogs as well as their biological shortcomings to propose next steps in the field of cancer therapy with these potent therapeutics. [ABSTRACT FROM AUTHOR]