Work

PROTAC for Bruton’s tyrosine kinase degradation alleviates inflammation in autoimmune diseases

Year: 2024

Type: article

Abstract: Proteolysis-targeting chimera (PROTAC) is a newly emerging strategy that harnesses the ubiquitin–proteasome system (UPS) to knock down target proteins for novel therapies 1 . This approach has rapidly garnered attention in both academia and industry fields. We designed the first PROTAC degrader to target Bruton’s tyrosine kinase (BTK), a key protein for B-cell survival and function, for the purpose of treating mutated BTK C481S- induced Ibrutinib-resistant B-cell malignancies 2 . We then developed a new generation of BTK degrader L18I through intensive ligand and linker optimizations, exhibiting improved solubility and superior efficiency in degrading BTK 3 . L18I exhibits excellent degradability towards different mutated forms of BTK proteins in human B-cell-derived non-Hodgkin lymphoma, and also inhibits the growth of activated human B-cell-like diffuse large B-cell lymphoma tumor cell in xenograft mice without obvious side effects 3 . Apart from these BTK-mediated B-cell tumor studies 4 , numerous evidence has highlighted the significant involvement of BTK dysfunction in autoimmune diseases 5 . Indeed, BTK inhibitors have been recently investigated for the treatment of autoimmune diseases, however, there are both successes and failures in clinical trials due to clinical efficacy and safety concerns 5 . Although PROTACs for BTK degradation have been shown minimal off-target effects as demonstrated in this report (Supplementary Fig. S1a–c ), and in our literature 2 , 3 , the application of BTK-targeting PROTACs in autoimmune diseases is lack. We studied the effects of the BTK degrader L18I on autoimmune diseases by using BM12 splenocytes-induced lupus disease model and the pristane-induced diffuse alveolar hemorrhage (DAH) disease model.

Source: Cell Discovery

DOI: 10.1038/s41421-024-00711-x