BTK inhibitors: past, present, and future.

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Bruton's tyrosine kinase (BTK) inhibitors have transformed B cell lymphoma treatment, notably in chronic lymphocytic leukemia (CLL).
• Ibrutinib, the first-in-class BTK inhibitor, paved the way, but newer covalent inhibitors offer improved safety profiles while still contending with resistance mutations.
• The emergence of noncovalent BTK inhibitors, like pirtobrutinib, marks a new phase, offering alternatives for relapsed/refractory CLL and prompting evaluation for upfront therapies.

Purpose of the Study:

• To review the latest advancements in Bruton's tyrosine kinase (BTK) inhibitor development.
• To explore the evolving landscape of BTK inhibitors, including covalent and noncovalent agents, and their potential applications.
• To discuss the future trajectory of BTK inhibitors and BTK degraders in treating B cell malignancies and autoimmune diseases.

Main Methods:

• Literature review of recent clinical trials and preclinical studies on BTK inhibitors.
• Analysis of drug resistance mechanisms associated with covalent BTK inhibitors.
• Evaluation of the efficacy and safety profiles of emerging noncovalent BTK inhibitors and BTK degraders.

Main Results:

• Covalent BTK inhibitors have shown improved safety but face resistance challenges.
• Noncovalent BTK inhibitors, such as pirtobrutinib, are gaining traction, with recent approvals for relapsed/refractory CLL.
• Newer BTK inhibitors and BTK degraders are under investigation for broader applications in B cell cancers and autoimmune conditions.

Conclusions:

• The field of BTK inhibitors is rapidly evolving, with noncovalent inhibitors poised to play a significant role.
• The optimal use of noncovalent BTK inhibitors, alone or in combination, for upfront treatment requires further determination.
• BTK inhibitors and degraders represent a promising therapeutic avenue for various B cell-related disorders and autoimmune diseases.