Inhibitors targeting Bruton's tyrosine kinase in cancers: drug development advances

Abstract

Bruton's tyrosine kinase (BTK) inhibitor is a promising novel agent that has potential efficiency in B-cell malignancies. It took approximately 20 years from target discovery to new drug approval. The first-in-class drug ibrutinib creates possibilities for an era of chemotherapy-free management of B-cell malignancies, and it is so popular that gross sales have rapidly grown to more than 230 billion dollars in just 6 years, with annual sales exceeding 80 billion dollars; it also became one of the five top-selling medicines in the world. Numerous clinical trials of BTK inhibitors in cancers were initiated in the last decade, and ~73 trials were intensively announced or updated with extended follow-up data in the most recent 3 years. In this review, we summarized the significant milestones in the preclinical discovery and clinical development of BTK inhibitors to better understand the clinical and commercial potential as well as the directions being taken. Furthermore, it also contributes impactful lessons regarding the discovery and development of other novel therapies.

Fig. 1. Key milestones in the target discovery and clinical development of BTK inhibitors, with United States’ FDA approved indications.

The BTK gene is first identified in 1993, and the BTK inhibitor ibrutinib is designed for clinical trials in 2009. It takes approximately 20 years from target discovery to new drug approval. As follows, the second-generation BTK inhibitors of acalabrutinib and zanubrutinib were launched in 2014, and approved by FDA in 2017 and 2019, respectively.

Fig. 2. Structure of BTK.

BTK is consisted by 659 amino acids, contains five domains, from N-terminal to C-terminal, domains are listed as the Pleckstrin homology (PH) domain, proline-rich TEC homology (TH) domain, SRC homology (SH) domain SH3, SH2, and the catalytic domain. Now, three approved BTK inhibitors are mainly targeted in the catalytic domain of the BTK.

Fig. 3. A schematic map of BTK in BCR signalling, TCR signalling, and chemokine receptor signalling pathway.

BTK is a crucial component of antigendependent BCR signaling that regulates B cell proliferation and survival. Meanwhile, BTK also participates in antigen-independent Toll-like receptor signaling and chemokine receptor signaling, regulates B cell adhesion, migration, and tumor microenvironment forces.

Fig. 4. Frequency of adverse events with ibrutinib, acalabrutinib, and zanubrutinib.

A The comparison of any grade adverse events in ibrutinib, acalabrutinib, and zanubrutinib. B The comparison of grade 3-5 adverse events in ibrutinib, acalabrutinib, and zanubrutinib.

Fig. 5. Global trends in BTK inhibitors.

A The indication distribution of BTK inhibitors in clinical trials of cancers; B The landscape of BTK inhibitors between 2005–2019; C The global status of BTK inhibitors in clinical trials of cancers.