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 inLs-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 |
| In vivo PK | Low bioavailability | No fasting |