Evaluation of Oral PROTAC Guidelines: Efflux Ratio Outweighs Chameleonicity Descriptors
Abstract
Oral bioavailability of PROTACs, which often fall outside the Rule-of-Five space, is still not perfectly understood. Thus, the design of orally bioavailable PROTACs remains challenging. Chameleonicity, the ability of a compound to adapt its conformation to different environments (solvent or membrane), has been suggested as a key molecular property. Here, using a diverse set of PROTACs from our portfolio, we evaluate whether published guidelines including predicted or experimental chameleonicity descriptors could refine AstraZeneca's internal guidelines for designing orally absorbed PROTACs. We did not find such a trend. Instead, reducing the efflux ratio in Caco-2 cells emerged as a useful addition to our guidelines.
Fields of Study & Subjects
Antiplatelet Therapy and Cardiovascular Diseases
Radiomics and Machine Learning in Medical Imaging
Gastroesophageal reflux and treatments
Publication details
- Journal / source
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Volume
- 17
- Issue
- 4
- Pages
- 890–899
- Publication date
- 31 March 2026
- Language
- EN