Novel BTK Degraders for Refractory Lymphoma: Targeting Catalytic and Allosteric Sites

Most refractory mantle cell lymphoma (MCL) patients experience disease progression after frontline therapy, with a median overall survival of 1-2 years after relapse. The most significant advance in MCL treatment was FDA approval of the covalent Bruton’s tyrosine kinase (cBTK) inhibitors ibrutinib (Wang et al., NEJM, 2013) and acalabrutinib (Wang et al., Lancet 2017), and the CAR-T therapy Tecartus (Wang et al, NEJM 2020) with the clinical trials led by Dr. Wang (Co-Investigator and Subaward PI of this proposal). However, MCL shows a high propensity for disease progression and relapse even after all these therapies initially succeed. Once relapsed, the MCL cells are more aggressive. Developing a next-generation targeted therapeutic strategy for the treatment of refractory lymphoma including resistant MCL is a vital need.