No images? Click here Hypha DiscoveryWhat's New Q3 2024Focus Features 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. Latest blog postNMR: An indispensable ADME tool Recent papers exploring the role of NMR spectroscopy in drug discovery and development have prompted us to look at at the role of NMR in drug metabolism studies. In the article we briefly discuss:
Recent paper picksAldehyde 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. Meet at CPHI Milan Going to CPHI Milan in October? Liam Evans will be there to discuss your metabolite and impurity synthesis, purification and identification needs. Visit us at booth 6SU94 or contact us to arrange a meeting. Stay tunedIf you're interested in keeping up with what's happening at Hypha Discovery, our blogs and paper picks, follow us on LinkedIn for regular updates. Metabolite Tales blogHave a look at our other blog articles we've published so far here. |