Which generation of targeted drugs does pirtobrutinib belong to?

Pirtobrutinib is a novel Bruton's tyrosine kinase (BTK) inhibitor that is widely used to treat a variety of B-cell malignancies. Compared with the first- and second-generation BTK inhibitors, pitobrutinib has significant structural and functional advantages and is classified as a third-generation BTK-targeted drug. It was originally designed to solve the problems of strong drug resistance and many side effects of previous generations of drugs.

The first-generation BTK inhibitors such as Ibrutinib are irreversible covalent binding inhibitors. Although effective, drug resistance often occurs in clinical practice. Especially when the C481 mutation occurs in the BTK protein, the drug cannot effectively bind to the target, resulting in a decrease in efficacy. Although the second-generation BTK inhibitors such as Acalabrutinib have improved some side effects, they are still covalent inhibitors and cannot completely solve the drug resistance problem. In contrast, pitobrutinib is a non-covalent, reversibly binding BTK inhibitor that can effectively act on a variety of BTK mutants including C481 mutations, breaking through the limitations of the first two generations of drugs.

Pitobrutinib has higher target selectivity and lower off-target toxicity, so it has shown good efficacy and tolerability in diseases such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). In some patients who have received multiple lines of treatment or are resistant to ibrutinib, pitobrutinib can still maintain a high response rate, which is the core value of it being regarded as a third-generation BTK inhibitor.
In general, as a third-generation BTK-targeted drug, pitobrutinib not only continues the effective mechanism of BTK pathway inhibition, but also achieves significant improvements in drug tolerability, safety and efficacy sustainability. With the advancement of multiple clinical studies around the world, this drug is expected to become an important choice for the treatment of relapsed and refractory B-cell lymphoma in the future, further promoting targeted therapy from "effective" to "precise".
Reference: https://go.drugbank.com/drugs/DB17472