Structure guided design of improved anti-proliferative rapalogs through biosynthetic medicinal chemistry

A combination of molecular modelling and rational biosynthetic engineering of the rapamycin polyketide synthase was used to generate rapalogs lacking O - and C -linked methyl groups at positions 16 and 17 respectively. These rapalogs displayed enhanced inhibition of cancer cell lines and were produc...

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Published in:Chemical science (Cambridge) 2013-01, Vol.4 (3), p.146-152
Main Authors: Gregory, Matthew A, Kaja, Andrew L, Kendrew, Steven G, Coates, Nigel J, Warneck, Tony, Nur-e-Alam, Mohammad, Lill, Rachel E, Sheehan, Lesley S, Chudley, Lindsey, Moss, Steven J, Sheridan, Rose M, Quimpere, Miguel, Zhang, Ming-Qiang, Martin, Christine J, Wilkinson, Barrie
Format: Article
Language:English
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Summary:A combination of molecular modelling and rational biosynthetic engineering of the rapamycin polyketide synthase was used to generate rapalogs lacking O - and C -linked methyl groups at positions 16 and 17 respectively. These rapalogs displayed enhanced inhibition of cancer cell lines and were produced at titres close to those of the parent strain. By recapitulating these experiments in higher-producing rapamycin strains, combined with the ectopic expression of gene products acting late in the biosynthetic pathway in order to minimise the accumulation of intermediates, gram-quantities of novel rapalogs bearing multiple structural changes were produced. Analysis of the FKBP12-rapamycin-FRAP crystal structure informed the design of new rapalogs accessible through bioengineering which display improved anti-proliferative activity.
ISSN:2041-6520
2041-6539
DOI:10.1039/c2sc21833j