Defining degradability landscape of protein degraders

Targeted protein degradation (TPD) is an emerging therapeutic modality. But how degradation efficacy is jointly determined by factors underlying this multi-step process is poorly understood. Here we present a succinct quantitative framework for modeling cellular mechanism of action of protein degraders, allowing for prediction of their cellular efficacy with practically obtainable parameters. Applying this model to published data on 41 different targets revealed a universal range of degradation rate around 1 min-1, which reflected the efficiency characteristic of TPD process. To provide a holistic characterization of degradation propensity of a target of interest, we define “degradability landscape”, and showed how it’s influenced by key factors. For kinase targets, we further quantified functional inhibition that enabled direct comparison between degrader and small molecule inhibitors. From above analysis, we derived several general guidelines for achieving potent degradation and proposed significant development opportunities of protein degraders from advantageous efficacy aspect.