Developing potent BTKC481S PROTACs for ibrutinib-resistant malignant lymphoma

Ibrutinib is a first-line treatment drug for B-cell malignancies. However, resistance to ibrutinib has been reported due to BTKC481S mutation. Although PROTAC strategy is expected to overcome this clinical resistance, it has limitations such as large molecular weight and moderate bioactivity, which restrict its potential clinical application. Herein, we report a new type of potent BTKC481S-targeting PROTAC degrader. Through design, computer-assisted optimization and SAR studies, we have developed a representative BTKC481S degrader L6 with a much smaller molecular weight and improved solubility. Notably, L6 demonstrates better BTK degrading activity and lower IC50 value in ibrutinib-resistant cell line than the first-generation BTK degrader P13I. Optimization strategy of L6 provides a general approach in the development of PROTACs targeting BTK and other proteins for future study.