Ranit Dutta, Anirudh Devarajan, Amelia Talluri, Ritam Das and S. Thayumanavan*,
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Proteolysis targeting chimera (PROTAC)-based degraders are highly potent pseudocatalytic drugs, but on-target off-site homing could yield undesirable consequences. We report here a generalizable AND-logic gated PROTAC, where the concurrent presence of two different disease-relevant endogenous stimuli liberates an active protein degrader. We design Dual-Action-Only PROTAC (DAO-PROTAC) molecules that are dormant and can only be activated in the presence of both hypoxia and cathepsin-L to degrade the protein of interest (POI). We also show that the dormancy of DAO-PROTACs translates to considerable mitigation of cytotoxicity, demonstrating the potential advantages over the corresponding free PROTAC and single-stimulus triggerable pro-PROTACs.
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The flagship journal of the American Chemical Society, known as the Journal of the American Chemical Society (JACS), has been a prestigious publication since its establishment in 1879. It holds a preeminent position in the field of chemistry and related interdisciplinary sciences. JACS is committed to disseminating cutting-edge research papers, covering a wide range of topics, and encompasses approximately 19,000 pages of Articles, Communications, and Perspectives annually. With a weekly publication frequency, JACS plays a vital role in advancing the field of chemistry by providing essential research.
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