Evaluation of covalent BTK inhibitors using COVALfinder®

BTK is a prominent therapeutic target for hematologic cancers and an attractive target for treating autoimmune diseases. BTK inhibitors can be divided into 2 types: covalent irreversible and non-covalent reversible inhibitors. Currently, 6 approved BTK inhibitors (Ibrutinib, Acalabrutinib, Zanubrutinib, Tirabrutinib and Orelabrutinib) target the kinase domain of BTK, forming a covalent bond with Cys481. Remibrutinib is another irreversible inhibitor that exhibits a good kinase selectivity due to binding to the non-phosphorylated form of BTK and is being evaluated in the clinic for urticaria and asthma. Recently, a hybrid inhibitor with the ability to establish a reversible covalent bond with Cys481 and temporarily inactivate BTK (Rilzabrutinib) has entered phase 3 clinical trials for the treatment of pemphigus and immune thrombocytopenic purpura. Here, we present the kinetic characterization of covalent BTK inhibitors using COVALfinder® as a successful approach to identify novel covalent drugs,  interpret SAR and modulate the safety profile of irreversible drugs.