Synthetic Strategies for Targeted AKR Degradation

Aldo-keto reductases (AKRs) are NAD(P)H-dependent oxidoreductases involved in carbonyl detoxification, steroid metabolism and cancer drug resistance. Among them, AKR1B10 is dysregulated in several solid tumors and can contribute to anthracycline resistance by reducing the C13 carbonyl group of these drugs to less active alcohol metabolites. Targeted protein degradation may offer advantages over conventional inhibition by eliminating both the catalytic and potential non-catalytic functions of the target protein. This contribution described the development of a first-generation PROTAC candidate targeting AKR1B10. Known inhibitors and virtual-screening hits were evaluated through molecular dynamics simulations, binding-energy calculations, exit-vector analysis and synthetic-feasibility assessment. Two warheads were selected and combined with PEG-like linkers of different lengths and a lenalidomide-derived cereblon recruiter, generating six candidate degraders. Computational modelling of the corresponding ternary complexes identified B06_P1 as the most promising design, owing to its stable and reproducible predicted AKR1B10–PROTAC–cereblon arrangement and favourable protein–protein interface. B06_P1 was subsequently synthesized and analytically characterized, confirming its identity and a purity above 97%. The compound represents a concrete chemical probe for the forthcoming evaluation of AKR1B10 binding and degradation, as well as its ability to restore cancer-cell sensitivity to anthracyclines.