Small molecules that modulate protein abundance through induced proximity expand the landscape beyond traditional inhibition. Here, we explore how introducing covalent or latent electrophilic groups into a multi-kinase binder scaffold reprograms protein abundance within the kinase family. Using the broad-spectrum kinase ligand TL13-87 as a template, we synthesize analogs bearing α-chloroacetamide, acrylamide, or terminal amine groups. Quantitative proteomics reveals that while most analogs have minimal global impact, MKI-AA, a multi-kinase inhibitor bearing an acrylamide warhead, uniquely stabilizes Aurora kinase A (AURKA). Mechanistic studies show that MKI-AA acts post-translationally to suppress AURKA ubiquitination and proteasomal degradation. Proteomic mapping of MKI-AA-induced AURKA interactors reveals changes in protein associations upon treatment, providing mechanistic insights into how MKI-AA influences AURKA stability. Intriguingly, adding a short linker to MKI-AA converts it from a stabilizer into a degrader, highlighting how subtle structural variations can invert functional outcomes.
Mozes et al. (Thu,) studied this question.