Description: Pirtobrutinib HCl (formerly known as LOXO-305; RXC 005), the hydrochloride salt of Pirtobrutinib, is a novel, potent, selective non-covalent / reversible Bruton's tyrosine kinase (BTK) inhibitor that is under investigation for the treatment of cancer. It is currently being studied in a global Phase 1/2 clinical trial. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells known as B-cells and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, mantle cell lymphoma and marginal zone lymphoma. Currently available BTK inhibitors irreversibly inhibit BTK and the long-term efficacy of these therapies has been limited by acquired resistance, most commonly through BTK C481 mutations, and intolerance, due to off target inhibition of other cellular targets. LOXO-305 was designed to reversibly bind BTK, preserve activity in the presence of the C481 acquired resistance mutations, and avoid off-target kinases that have complicated the development of both covalent and investigational non-covalent BTK inhibitors. In Feb 2023, FDA approved Pirtobrutinib for treating Non-Hodgkin lymphoma.

References: J Clin Oncol. 2015; 35:1437-1443; Haematologica. 2018; 103(5):874-879