Development of proteolysis targeting chimeras (PROTACs) is emerging as a promising strategy for targeted protein degradation. However, the drug development using the heterobifunctional PROTAC molecules is generally limited by poor membrane permeability, low in vivo efficacy and indiscriminate distribution. Herein an aptamer‐PROTAC conjugation approach was developed as a novel strategy to improve the tumor‐specific targeting ability and in vivo antitumor potency of conventional PROTACs. As proof of concept, the first aptamer‐PROTAC conjugate (APC) was designed by conjugating a BET‐targeting PROTAC to the nucleic acid aptamer AS1411 (AS) via a cleavable linker. Compared with the unmodified BET PROTAC, the designed molecule (APR) showed improved tumor targeting ability in a MCF‐7 xenograft model, leading to enhanced in vivo BET degradation and antitumor potency and decreased toxicity. Thus, the APC strategy may pave the way for the design of tumor‐specific targeting PROTACs and have broad applications in the development of PROTAC‐based drugs.

No abstract

Autophagosome-tethering compounds (ATTECs) are an emerging new technology in targeted protein degradation. However, effective tools and successful examples for autophagosome-tethering chimeras are still rather limited. Herein, ATTEC ispinesib was identified for the first time to be an effective warhead to design autophagosome-tethering chimeras. As a conceptual validation study, the first generation of autophagic degraders of nicotinamide phosphoribosyltransferase (NAMPT) were developed by connecting the NAMPT inhibitor and LC3-binding ispinesib through a flexible linker. In particular, compound A3 significantly induced the degradation of NAMPT through the autophagy-lysosomal pathway, leading to excellent cellular antitumor potency. Ispinesib may have broad applications in the design of potent autophagosome-tethering chimeras.

…i sa ne merging new technology in drug discovery.I nt heir Research Article on page 23299, Guoqiang Dong, Chunquan Sheng et al. developed the first aptamer-PROTACc onjugate (APC), which showed improved tumor targeting and in vivo protein degradation, leading to enhanced antitumor potencya nd decreased toxicity.

Development of proteolysis targeting chimeras (PROTACs) is emerging as ap romising strategy for targeted protein degradation. However,the drug development using the heterobifunctional PROTACmolecules is generally limited by poor membrane permeability,l ow in vivo efficacy and indiscriminate distribution. Herein an aptamer-PROTACconjugation approach was developed as an ovel strategy to improve the tumor-specific targeting ability and in vivo antitumor potency of conventional PROTACs.A sp roof of concept, the first aptamer-PROTACc onjugate (APC) was designed by conjugating aB ET-targeting PROTACt ot he nucleic acid aptamer AS1411 (AS)v ia ac leavable linker. Compared with the unmodified BET PROTAC, the designed molecule (APR)s howed improved tumor targeting ability in aM CF-7 xenograft model, leading to enhanced in vivo BET degradation and antitumor potency and decreased toxicity. Thus,t he APC strategy may pave the way for the design of tumor-specific targeting PROTACs and have broad applications in the development of PROTAC-based drugs.