Key result
Reducing Caco-2 efflux ratio outperforms chameleonicity descriptors in designing orally bioavailable PROTACs.
Why the study?
Oral bioavailability of PROTACs is not perfectly understood and their design remains challenging, leading to the question of whether chameleonicity descriptors can refine design guidelines.
For designing orally bioavailable PROTACs, reducing the efflux ratio in Caco-2 cells is a more useful strategy than relying on chameleonicity descriptors.
Favors Caco-2 efflux ratio reduction over chameleonicity for oral PROTAC bioavailability; challenges descriptor reliance and should inform future design.
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.
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Manach et al. (2026) studied this question. Reducing the efflux ratio in Caco-2 cells outweighs chameleonicity descriptors as a useful strategy for designing orally bioavailable PROTACs.
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