Proteolytic Targeting chimeras (PROTACs) are heterobifunctional molecules that induce degradation of endogenous proteins through E3 ligase-mediated ubiquitination. Their cytotoxicity at low concentrations against several cancer cell lines makes them promising candidates for cancer therapeutics. Nevertheless, PROTACs often display low cell penetration and low solubility, making them poor pharmaceutical candidates. Moreover, the catalytic nature of PROTAC-induced protein degradation, and the ability of PROTACs to degrade proteins through transient interactions outside of well-defined binding pockets, leads to unpredictable off-target effects, complicating their clinical translation. We have developed bottlebrush polymer prodrugs (BPDs) as a novel class of therapeutic agents with antibody-like sizes, tunable aspect ratios, advanced linker chemistry for prodrug activation, and the ability to incorporate active targeting agents. Here, we leverage the synthetic modularity of this platform to synthesize BPDs of the PROTAC ARV825 with linkers optimized to activate in tumor tissue. We demonstrate that our PROTAC-BPD displays cytotoxicity in MM1.S multiple myeloma cell lines. Quantitative proteomics reveals lowered BRD4 levels and was ascertained to have undergone degradation via the ubiquitin-proteasome pathway. This work offers a new strategy to circumvent the challenges of PROTAC translation using a safe, scalable, and well-defined prodrug platform.

PROTAC-conjugated bottlebrush polymers for systemic drug delivery

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.