Bruton tyrosine kinase (BTK) is a non-receptor kinase and plays a crucial role in carcinogenic signal transduction. Carcinogenic signal transduction is crucial for the proliferation and survival of leukemia cells in many B-cell malignancies. Meanwhile, the B cell antigen receptor signal is activated in secondary lymphoid organs and drives the proliferation of malignant B cells, including chronic lymphocytic leukemia (CLL) cells. Nonetheless, BTK is a key component of B cell receptor (BCR) signal transduction that regulates B cell proliferation and survival. BTK showed phosphorylation in vitro after stimulation of the B cell antigen receptor (BCR), followed by a higher level of kinase activity. Besides, BTK plays a variety of roles in monocytes of the innate immune system, especially in dendritic cells and macrophages.

Moreover, BTK plays a role in Toll-like receptor-mediated infection factor recognition, cell maturation and recruitment, and Fc receptor signal transduction. Furthermore, BTK is a direct regulator of NLRP3 inflammatory corpuscles, the key mechanism of congenital inflammation. In addition, BTK plays a role in several bone marrow cell populations that represent an important component of the tumor microenvironment. Therefore, at present, people are very interested in BTK inhibition as an anticancer therapy, not only in B-cell malignant tumors but also in solid tumors. The small molecule inhibitor of BTK showed antitumor activity. Today, we will introduce a highly selective and non-covalent next-generation BTK inhibitor — Pirtobrutinib.

Pirtobrutinib (LOXO-305) is a Highly Selective and Non-covalent BTK Inhibitor.

At first, Pirtobrutinib (LOXO-305) inhibits diverse BTK C481 substitution mutations. Specifically, Pirtobrutinib causes regression of BTKdependent lymphoma tumors in mouse xenograft models. Importantly, Pirtobrutinib is also more than 300-fold selective for BTK versus 370 other kinases tested. Pirtobrutinib shows no significant inhibition of non-kinase off-targets at 1 μM.

Secondly, Pirtobrutinib potently inhibits both wild-type BTK and BTK C481S-mediated kinase activity with nanomolar potency. Particularly, Pirtobrutinib inhibits WT BTK (Y223) autophosphorylation with an IC50 of 3.68 nM. Obviously, Pirtobrutinib inhibits BTK C481S Y223, C481T Y223, and C481R Y223 autophosphorylation with IC50 values of 8.45, 7.23, and 11.73 nM, respectively.

Finally, Pirtobrutinib (LOXO-305) is a highly selective and non-covalent next-generation BTK inhibitor.


[1]   Gomez E B , et al. Blood, 2019, 134(Supplement_1):4644-4644.