Emerging Options May Help Address Challenges With Traditional BTK-Inhibitor Treatment in Lymphomas

Bruton tyrosine kinase (BTK) have proved to be one of the most effective treatments for several B-cell malignancies, such as chronic lymphocytic leukemia and non-Hodgkin lymphoma, since ibrutinib entered the market. However, improvements are needed as drug resistance and off-target induced side effects remain. But authors of one recent paper, published in the European Journal of Medicinal Chemistry, say a certain type of BTK inhibitor may pose a solution.

According to the researchers, BTK inhibitors can be split into 2 categories, “distinguished by the formation of a covalent bond between the ligand and the Cys481 residue of the BTK binding side.”

The researchers suggest that reversible BTK inhibitors may play a key role in treatment when it comes to addressing resistance stemming mutations in the active site (Cys481) that emerge from treatment with irreversible BTK inhibitors like ibrutinib.

“The crucial mutation at Cys481 from cysteine to serine activates downstream signals that promote the activation of distal B-cell receptor (BCR) modules and subsequently leads to tumor cell proliferation and migration, thus bypassing the inactive BTK step,” explained the researchers.

“The approved BTK inhibitors all target Cys481 of BTK, thereby simply switching to another BTK inhibitor may be ineffective when resistance emerges,” they continued. “Developing reversible BTK inhibitors that do not rely on the covalent bond formation with Cys481 has been suggested as a possible solution to address the resistance induced by a Cys481 mutation.”

The reversible BTK inhibitor pipeline is ripe, with multiple inhibitors in pre-clinical development, including imidazopyrazine analogs, thiazole analogs, pyrrolopyrimidine analogs, and pyrimidine and triazine analogs.

Irreversible BTK inhibitors in pre-clinical development span various categories, including:

• pyridine carboxamide analogs
• pyramid analogs
• dithiocarbamate analogs
• 1,3,5-Triazine analogs
• pyrazolo[3,4-d] pyrimidinyl analogs
• pyrrolo[3,4-d]pyrimidinyl analogs

“Designing BTK inhibitors with target selectivity and minimal off-target effects is challenging, but immense progress has been made in advancing BTK inhibitors with desirable drug-like properties into the clinic,” researchers explained.

Another potential solution for overcoming ibrutinib resistance posited by the researchers includes combining BTK inhibitors with other classes of treatment, including chemotherapeutics, antibodies, targeted treatments, or immunotherapies. The researchers noted that relevant clinical trials are ongoing and “positive preliminary clinical results have been collected.”

Reference: Liu J, Chen C, Wang D, Zhang J, and Zhang T. Emerging small-molecule inhibitors of the Bruton’s tyrosine kinase (BTK): current development. Eur J Med Chem. Published online March 12, 2021. doi:10.1016/j.ejmech.2021.113329