Highly cytotoxic natural products and related derivates are potential candidates as payloads for ADCs.
Creative Biolabs has experts in small molecule drug development and has developed a variety of ADCs using DNA-damaging drugs.
DNA-damaging agents have a long history of utilization in cancer chemotherapy, eliminating tumor cells, reducing tumor growth and alleviating pain. Compounds modifing DNA bases, intercalating between bases, or forming crosslinks in DNA are one class of DNA-damaging agents. Nitrogen mustards and their derivatives, such as DNA alkylators cyclophosphamide, melphalan and chlorambucil, have been developed. They act by alkylating DNA on purine bases directly, resulting in stalled replication fork progression and cell death. The natural DNA-alkylating agents (e.g. mitomycin C and streptozotocin) and alkylating-like platinum agents are also discovered and have positive effects upon anticancer drug researches. The second class of DNA-damaging agents is antimetabolites, which mimics normal cellular molecules and interferes with DNA replication. These agents are usually DNA antagonists (e.g. pyrimidine analogs 5-ﬂuorouracil (5-FU), ﬂoxuridine, gemcitabine and purine analogs) to block nucleotide metabolism pathways. For instance, the incorporation of purine analogs can prevent proper nucleobase addition and consequently cause DNA replication failed. To target protein-DNA complexes is an alternative method to interfere DNA function. There are various proteins playing crucial roles in DNA processes including replication, recombination, etc. So interfering DNA-protein binding is the mechanism of action of many DNA-active drugs, such as topoisomerases poisons. In the present development of ADCs, some kinds of DNA-damaging agents, such as calicheamicins, CC-1065 analogs and duocarmycins, have been widely explored as ADC payloads due to their potent cytotoxicity. They function by binding to the minor groove of DNA and inducing diradical or reacting with adenine residues as DNA alkylators which can result in double strand DNA cleavage and cell death. Compared to toxins targeting tubulin ﬁlaments, the cytotoxins of this class can kill target cells at any point in their life cycle. The first ADC approved by the FDA, gemtuzumab ozogamicin, uses a derivative of calicheamicin as the payload and is proved to be effective in relapsed acute myeloid leukemia, which suggests that these drugs targeting DNA have potential to be developed as conjugates for ADCs.