▎WuXiEdited by the Kant Content Team

Last November, patients with sickle cell disease (SCD) welcomed the first approved CRISPR/Cas9 gene-editing therapy, named Casgevy, which works by editingBCL11AGenes, upregulate the expression of fetal hemoglobin (HbF).Approval of CasgevyIt is a major breakthrough in the field of gene editing and also brings hope of a potential cure for SCD patients. However, most SCD patients need a treatment that is more convenient to take and has higher accessibility. Recently,Scientists at Novartis Biomedical Research published their latest study in the top academic journal *Science*, describing a molecular glue protein degrader targeting WIZ. By degrading WIZ, it can also upregulate HbF expression, achieving the therapeutic effect for SCD.The comment article published in "Science" stated that this brings hope for the development of innovative oral therapies for SCD.

After a series of chemical optimizations, scientists developed two selective WIZ molecular glue degraders, dWIZ-1 and dWIZ-2. In humanized mice and non-human primate models, these two molecular glue degraders not only successfully induced HbF expression but also demonstrated good tolerability.

One of the senior authors of the article, Dr. Jay Bradner, former head of Novartis Biomedical Research, tweeted that this study represents multiple breakthroughs. This isWZ Transcription Factor Identified as a Repressor of HbF Expression for the First Time. This also represents another breakthrough in targeting undruggable proteins. WIZ is a transcription factor without a traditional small-molecule drug-binding pocket, and even AlphaFold cannot predict an effective tertiary structure. Research shows,Molecular glue protein degraders mediate the degradation of WIZ protein by targeting the zinc finger secondary structure of the WIZ transcription factor, offering a new strategy for tackling undruggable targets.

Dr. Bradner also stated that, most importantly, this research brings hope for the development of a safe, effective, and highly accessible oral SCD medication for patients with SCD.

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