Mutasynthesis of C17- and C21-Substituted Ansamitocins for Use as ADC Payloads
journal contribution
posted on 2025-09-11, 23:44 authored by Anna E. Stanley-Smith, Nigel Coates, James C. Fox, Frank Delfino, Sylvia Degrado, Arthur Kunz, Shu Mao, Feng Zhao, Ben Garforth, Adam Hold, Hui Hong, John Kendall, Jessica Lane, Coline Meï, Annabel Murphy, Joanna Pogwizd, Celia Ruiz Escobar, Benjamin Wertz, Steven J. Moss, Matthew A. Gregory, Thomas NittoliStrain engineering
and process improvement were used
to improve
the titer of mutasynthetically generated ansamitocins generated by
feeding 3-amino-5-hydroxybenzoic acid (AHBA) analogs to cultures of Actinosynnema pretiosum inactivated in AHBA biosynthesis.
Ansamitocin analogs with fluorine and bromine substituents at C17
and C21 were then generated by feeding hydroxylated AHBA analogs.
Fully processed C17 and C21 fluoro and bromo ansamitocins had cytotoxic
activity similar to that of Ansamitocin P3. The C21 fluoro derivative
was converted to a cytotoxic payload and an antibody drug conjugate
(ADC).
History
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