Uncialamycin as a novel payload for antibody drug conjugate (ADC) based targeted cancer therapy

Anthraquinone-fused enediynes: discovery, biosynthesis and development

“…Thus, ADCs have emerged as a promising anticancer therapy recently by combining a tumor targeting antibody and highly cytotoxic payload via a chemical The Chowdari group synthesized two UCM analogues (140 and 141) with an NH 2 group at the C8 position. 104 Both compounds exhibited much higher potency than MMAE, the payload used in the FDA approved ADC Adcetris. Because 141 has better chemical reactivity, it was chosen to append different linkers.…”

“…In contrast, the 146conjugated ADCs were not active on either cell lines, probably due to the non-cleavable nature of the linker. 104 Poudel and co-workers addressed the mouse serum instability issue of the UCM linker-payload by modifying different parts of the linker and payload. Ultimately, a linker-payload (144) containing valine-citrulline with a self-immolating mamide p-aminobenzyl carbamate (MA-PABC) was found to be resistant to serum hydrolysis but sensitive to intracellular protease cleavage (Fig.…”

Antibody-Drug Conjugates: The New Frontier of Chemotherapy

“…In addition to all of the above-mentioned payloads, other molecules available also act as DNA-damaging agents for incorporation into newly emerging ADCs. Among these compounds, particular mention should be given to iSGD-1882 (DNA minor groove cross-linker derived from PBD dimers), centanamycin (binds to DNA and alkylates or intercalates into DNA), PNU-159682 (an anthracycline metabolite) [ 69 ], and uncialamycin (an enediyne natural product isolated from Streptomyces uncialis) [ 70 ], all active on different cancer cell lines, and finally indolinobenzodiazepine dimers (IGNs) bind to the DNA minor groove leading to DNA cross-linking [ 71 ].…”

Potential drugs used in the antibody–drug conjugate (ADC) architecture for cancer therapy

“…Besides the abovementioned payloads, other molecules, which can be used as a DNA‐damaging agent in ADC synthesis, include SGD‐1882 (a cytotoxic DNA minor groove cross‐linking derivative of PBD dimers which is not an MDR1 substrate) (Kim & Kim, ), centanamycin (an indolecarboxamide synthesized as a less toxic analog of CC‐1065 and duocarmycin which binds to DNA and alkylates or intercalates into the DNA) (Beck et al, ; Kim & Kim, ), PNU‐159682 (a highly potent metabolite of the anthracyclines which shows three folds more cytotoxicity compared with doxorubicin) (Yu et al, ), and uncialamycin (an enediyne natural product isolated from the Streptomyces uncialis ) (Chowdari et al, ), all showing acceptable potency against a broad range of cancer cell lines. Indolinobenzodiazepine dimers, also known as IGNs, are an indolino‐benzodiazepine dimer consisting of a mono‐imine moiety, representing a novel set of cytotoxic agents with highly potent activity in vitro (an IC50 value of low pM) against a variety of cancer cells.…”