Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a major therapeutic target [2]. It is fundamental in B-cell survival, playing a crucial role in the B-cell receptor (BCR) pathway [3,4,5]. BTK is central to the survival of both malignant and normal B lymphocytes, making it significant in B-cell-driven malignancies and autoimmune disorders [3,4].

BTK inhibitors have revolutionized the treatment of B-cell lymphomas like chronic lymphocytic leukemia (CLL) [1]. First-in-class ibrutinib has been succeeded by covalent BTK inhibitors, and the non-covalent pirtobrutinib was recently approved for relapsed and refractory CLL [1]. Pirtobrutinib, a highly selective non-covalent inhibitor, binds BTK in the adenosine triphosphate binding region, inhibits both BTK and BTK C481 substitution mutants, and uniquely stabilizes BTK in an inactive conformation [2]. Resistance mutations are a challenge; for example, ibrutinib is susceptible to C481 mutations, while non-covalent inhibitors like pirtobrutinib are vulnerable to other mutations such as at residues Threonine 474 and Leucine 528 [4].

In conclusion, BTK is essential for B-cell survival and a key player in the BCR pathway. Its inhibition has shown great promise in treating B-cell malignancies and autoimmune disorders. The development of BTK inhibitors, despite facing challenges like resistance mutations, has significantly advanced the treatment landscape of related diseases [1,2,3,4].

References:

1. Cool, Allison, Nong, Tiffany, Montoya, Skye, Taylor, Justin. 2024. BTK inhibitors: past, present, and future. In Trends in pharmacological sciences, 45, 691-707. doi:10.1016/j.tips.2024.06.006. https://pubmed.ncbi.nlm.nih.gov/39025681/

2. Gomez, Eliana B, Ebata, Kevin, Randeria, Hetal S, Allerston, Charles K, Brandhuber, Barbara J. . Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor. In Blood, 142, 62-72. doi:10.1182/blood.2022018674. https://pubmed.ncbi.nlm.nih.gov/36796019/

3. Leitinger, Dr Emma, Kaplan, Dr Zane. 2022. BTK Inhibitors in Haematology: Beyond B Cell Malignancies. In Transfusion medicine reviews, 36, 239-245. doi:10.1016/j.tmrv.2022.06.009. https://pubmed.ncbi.nlm.nih.gov/36376164/

4. Nawaratne, Vindhya, Sondhi, Anya K, Abdel-Wahab, Omar, Taylor, Justin. . New Means and Challenges in the Targeting of BTK. In Clinical cancer research : an official journal of the American Association for Cancer Research, 30, 2333-2341. doi:10.1158/1078-0432.CCR-23-0409. https://pubmed.ncbi.nlm.nih.gov/38578606/

5. Schaff, Lauren, Nayak, Lakshmi, Grommes, Christian. 2024. Bruton's tyrosine kinase (BTK) inhibitors for the treatment of primary central nervous system lymphoma (PCNSL): current progress and latest advances. In Leukemia & lymphoma, 65, 882-894. doi:10.1080/10428194.2024.2333985. https://pubmed.ncbi.nlm.nih.gov/38597202/