P7I-2

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 clin. resistance, it has limitations such as large mol. weight and moderate bioactivity, which restrict its potential clin. application.Herein, we report a new type of potent BTK^C481S -targeting PROTAC degrader.Through design, computer-assisted optimization and SAR studies, we have developed a representative BTK^C481S degrader L6 with a much smaller mol. weight and improved solubilityNotably, 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.