The irreversible inhibitor Ibrutinib for Bruton’s tyrosine kinase (BTK) has emerged as a transformative treatment option for patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies. However, more than 80% of CLL patients develop resistance due to the mutant site in cysteine to serine covalently bound by Ibrutinib (C481S). Recently, Alexandru D. Buhimschi, identified and discovered a BTK inhibitor MT-802 based on PROTAC technology.



In previous blogs, we have introduced several PROTAC degraders; MT-802 is the first BTK inhibitor we introduced.

MT-802 binds fewer off-target kinases than Ibrutinib. In addition, MT-802 exhibits equivalent activity (>99% degradation at nanomolar concentrations) against wild-type and C481S BTK. In vitro, MT-802 is able to reduce the phosphorylated BTK with pool activity in C481S mutant cells, whereas Ibrutinib cannot.

Furthermore, MT-802 exhibited a DC50 of 9.1 nM for BTK with maximal degradation being observed by 250 nM. The authors also compared the compound to Ibrutinib nor SJF-6625. As a result, unsurprisingly, neither Ibrutinib nor SJF-6625 were able to induce BTK degradation, demonstrating that MT-802 id required to bind tp cereblon. Moreover, MT-802 completely degraded BTK as early as 4 hours, with half of the total BTK degraded after approximately 50 minutes. Therefore, MT-802 is a not only potent but also rapid degrader of BTK.

To conclude, MT-802 is a potent BTK degrader based on PROTAC technology, with a DC50 of 1 nM. MT-802 has potential to treat C481S mutant chronic lymphocytic leukemia (CLL).

Buhimschi AD, et al. Targeting the C481S Ibrutinib-Resistance Mutation in Bruton’s Tyrosine Kinase Using PROTAC-Mediated Degradation. Biochemistry. 2018 Jul 3;57(26):3564-3575.