BTK is intimately involved in multiple signal-transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. BTK has become a target of interest for treating chronic lymphocytic leukemia owing to its crucial role downstream of the B cell receptor critical for proliferation and survival of leukemic cells, indicating its relevancy as a target for B cell malignancies. Since it was first described in 1993, multiple BTK inhibitors (BTKi) have since been developed. The irreversible BTK inhibitor ibrutinib was discovered in the early 2000s and became the first FDA-approved BTKi in 2013. Ibrutinib is associated with high response rates in relapsed/refractory chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL) and in chronic graft versus host disease. Ibrutinib binds to a non-conserved cysteine residue (Cys481) located adjacent to the ATP-binding site in BTK and its selectivity for BTK is derived from the presence of Cys481 since few kinases possess a homologous cysteine. Several other covalent BTK inhibitors have been approved or are in clinical trials, containing a variety of Michael acceptors as alternatives to the acrylamide warhead in ibrutinib. Acalabrutinib and zanubrutinib were approved by the US FDA in 2019 108 and 2023 109 ; they showed improved selectivity and exhibited fewer adverse effects than ibrutinib. Acalabrutinib contains a butyramide electrophile instead of an acrylamide. The butyramide electrophile is less reactive than the acrylamide warhead of ibrutinib, which is proposed to account in part for its improved selectivity for BTK and the reduced number of adverse cardiovascular events. Acalabrutinib was approved in 2017 for MCL and in 2019 for CLL. With higher selectivity than ibrutinib, acalabrutinib inhibits only BTK and has no effect on other kinases such as TEC, BMX, and TXK. Interestingly, ACP-5862, the major metabolite of acalabrutinib, also covalently inhibits BTK while exhibiting two-fold lower potency than acalabrutinib but similar selectivity towards BTK. Current data suggest that ACP-5862 may be clinically relevant to the efficacy of acalabrutinib therapy while retaining its high BTK selectivity. JS25 is a 2 nd generation covalent BTK inhibitor with nanomolar potency against BTK (5.8 nM) derived from structural modification of BMX-IN-1, a recently discovered inhibitor of BTK. 116 JS25 binds covalently to BTK at Cys481 and selectively inhibits BTK. JS25 presented a broad spectrum of activity in myeloid and lymphoid B-cell cancers and demonstrated improved therapeutic efficacy versus ibrutinib in patient-derived diffuse large B-cell lymphoma (DLBCL) models, as well as in xenograft models of B-cell lymphoma (BL) and CLL. 116 JS25 also possesses the potential to treat metastatic forms of blood cancers in the brain because of its permeability of blood-brain barrier. JS25 is likely to be a therapeutically relevant BTKi, with demonstrated antiproliferative effects and an improved selectivity profile, for clinical use against hematological cancers and autoimmune diseases). 116