Drug Metabolism Studies of PROTAC Molecules

PROTAC/Molecular Glue Services

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Time: 2022-08-23

Source: Viva Biotech

[Abstract]:

PROTACs are bifunctional compounds, an emerging modality, with molecular weights and physicochemical properties that fall outside the classic ‘rule-of-five’ spaces of small-molecule property. In the drug discovery of PROTACs, consequently, there are complex challenges including DMPK, compared with traditional small molecules. Our DMPK group provides flexible, customized services in support of overcoming the challenges in developing oral PROTEC drugs.

Common problems and solutions for DMPK evaluation of PROTAC molecules:

DMPK	Issue	Recommendation
Solubility	Insoluable	Simulated fluid replace PBS buffer
Permeability	Poor recovery	Addition of BSA, FBS
Transporter	Substrate, or inhibitor	Specific transporter, hMDR1 Knockin MDCKll Cells Or, hBCRP Knockin MDCKll Cells
Bioanalysis	Unstable	Deactivate enzyme in plasma or blood immediately
Bioanalysis	Non specific binding	Detergent
Bioanalysis	Fragment in LC-MS ion source	Optimized MS condition
Metabolism	Diverse metabolism	Comprehensive metabolism system: microsome, hepatocyte, S9, cytosol; AO, UGT activity; CYP phenotyping
PPB	Unstable	Enzyme inhibitor

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