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 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.