Late-Stage Functionalisation of Drug Candidates using PolyCYPs Enzymes

Introducing oxygen into a drug candidate late in the optimisation process has several applications including exploration of SAR (structure-activity relationships) and the ability to access derivatives that may possess superior properties such as improved metabolic stability and LLE (ligand-lipophilicity efficiency). Biocatalysis can provide access to chemical space in a complementary manner to chemical synthesis and provide a “one-experiment” solution to accessing multiple derivatives in parallel. This poster illustrates the application of a new biocatalysis kit, PolyCYPs®, to enable parallel synthesis of hydroxylated derivatives of drugs.

The PolyCYPs platform is comprised of a set of cloned cytochrome P450 enzymes and redox partners derived from some of the most talented bacteria in Hypha’s biotransformation panel. Enzymes in the kit catalyse oxidation reactions of a wide variety of substrate types to generate multiple derivatives in one pot, including hydroxylated and dealkylated derivatives useful for diversification and late stage functionalization of drug leads.

This case study compares the hydroxylated derivatives produced from a drug candidate under development by AstraZeneca using a whole cell microbial approach with those obtained employing selected PolyCYPs enzyme reagents, as part of a study exploring the effect of different polar chemical space on potency.