JS25, a Selective and Covalent BTK Inhibitor, Acts by Segregating Tyr551
Posted On 2022-11-26
BTK, Bruton’s tyrosine kinase, belongs to the cytoplasmatic kinases TEC subfamily. BTK involves in immune regulation, and is activated by Src kinases. Then BTK leads to phospholipase-Cγ (PLCγ) phosphorylation, Ca2+ mobilization, and NF-κB/MAP activation. Meanwhile, BTK increases proinflammatory cytokines IL-6 and IL-10 production and controls integrin-mediated B-cells adhesion. Moreover, BTK promotes B-cell development, serves as a key regulator, and B-cell-related malignancies are effective drug targets. For example, BTK expression is down-regulated in numerous hematological cancers, such as leukemia, lymphoma, and myeloma. Here, we’ll introduce a selective and covalent BTK Inhibitor, JS25.
JS25 Inhibits BTK by Selectively Segregating Tyr551.
Specifically, JS25 (0-100 nM; 0-60 min) has a higher BTK inhibition potency compared to Ibrutinib, Acalabrutinib, and BMX-IN-1. They have irreversible binding efficacy (Ki values) for BTK of 0.77 nM, 0.59 nM, 1.29 nM, and 15.07 nM, respectively. Furthermore, JS25 (10 μM; 4 h and 15 h) degrades BTK and inhibits it (IC50=28.5 nM) by conducting Tyr551 “sequestration”. As a result, JS25 makes BTK unable to phosphorylation in cells. JS25 (0-100 μM; 72 h) widely suppresses cell proliferation of blood cancer cell lines with IC50s of 0.5-38.0 μM. JS25 has permeability to cross the blood-brain barrier but also has stability in the HBEC-5i cell model (in vitro). On the whole, JS25 has great durability in the treatment.
Importantly, JS25 exhibits “on-target” cytotoxicity against viable diffuse large B-cell lymphoma (DLBCL). And JS25 (10 mg/kg and 20 mg/kg; i.p.; every 2 days for 14 d) leads to subcutaneous tumor reduction in the murine xenograft model with Burkitt’s lymphoma. JS25 also causes metastatic and secondary tumor formation suppression. JS25 (1 μM, 2.5 μM, and 5 μM; injection; daily for 2 d) also decreases tumor burden in zebrafish with chronic lymphocytic leukemia.
Above all, JS25 segregates Tyr551 to decrease p-BTK. JS25 is well crossing the blood and brain barrier and inhibits tumor growth. JS25 is a potential drug targeting hematological cancers.
 Sousa B B, et al. ACS Pharmacology & Translational Science, 2022.