Metabolism of degraders

We take a look at the growing knowledge about metabolism of targeted protein degraders drugs such as PROTACs.

Both phase I metabolism and glucuronidation have been observed as routes of metabolism of PROTACs, including a not unsurprising involvement of CYP3A4. However metabolism by AO and UGTs can also be a significant clearance route, as well as amidase/esterases. 

Unusual fecal metabolites

Hypha worked with scientists at Genentech to generate and elucidate the structures of novel metabolites of inavolisib (GDC-0077), which had been observed in human feces.

It turns out M18 and M19 are conjugated with part structures of stercobilin, a microbial metabolite of bilirubin found in the gut which imparts the brown color to feces. To our knowledge this type of drug conjugate has not been reported before.

Aldehyde oxidase-mediated DDI 

Where metabolic pathways have not been interrogated for drugs in development, unwelcome surprises may arise. Scientists recently uncovered a major role for aldehyde oxidase (AO) in the metabolism of quinoline-containing OSI-930, and demonstrated an AO-mediated DDI (drug-drug interaction) arising from inhibition of the enzyme by erlotinib.

Intramolecular reactions and chemical degradation

Here we highlight a paper describing how a single biotransformation event led to several unusual metabolites proposed to arise from intramolecular reactions and chemical degradation of a key reactive metabolite following a single CYP-mediated biotransformation of the pyrazole moiety in the drug.