Heterobifunctional proteomimetic polymers for targeted degradation of MYC and KRAS

Targeted protein degradation has unlocked new strategies for modulating previously undruggable proteins; however, existing small molecule approaches are challenging to optimize and largely limited to targets with ligandable pockets. To overcome these challenges, we introduce the HYbrid DegRAding Copolymer (HYDRAC), a polymer-based platform that integrates target-binding peptides with peptide or small-molecule degrons for the selective degradation of disease-relevant proteins. HYDRACs are synthesized easily, exhibit structural tunability, and facilitate the attachment of multivalent payloads. The modular payload capability accommodates diverse target-binding motifs and E3 ligase recruiters—such as VHL, KEAP1, and CRBN—broadening the design space. We apply HYDRACs against two historically intractable targets, MYC and KRAS, achieving robust degradation in vitro and sustained tumor inhibition in murine models. Notably, HYDRACs containing consensus RAS-binding motifs effectively degrade KRAS in cells harboring different alleles, suggesting pan-KRAS potential. We envision the HYDRAC platform as a generalizable approach, greatly expanding the armamentarium for TPD. Overall design: To investigate effects of MYC-degrading HYDRACs, as well as scrambled sequence (non-targeting) controls, on cellular transcriptional programs in order to ascertain target-engagement and selectivity, we performed gene expression profilling analysis using data obtained from RNA sequencing of PC3 cell line treated for 24 hours with Vehicle (DMSO) or 5 uM of HYDRAC or scrambled negative control. RNAseq profiling of wild-type PC3, A549 and MycCaP cells treated with HYDRAC and negative control (nontargeting polymer, denoted as sHR) for 24 hours treatment. As well as PC3 cells treated with genetic knockdown of MYC (siMYC and siCNT).