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Review
. 2021 Aug 3;11(8):764.
doi: 10.3390/jpm11080764.

Non-Covalent BTK Inhibitors-The New BTKids on the Block for B-Cell Malignancies

Katharine L Lewis  1   2   3 , Chan Y Cheah  1   2   3   4
Affiliations
Review

Non-Covalent BTK Inhibitors-The New BTKids on the Block for B-Cell Malignancies

Katharine L Lewis et al. J Pers Med. .

Abstract

The B-cell receptor signalling pathway plays a critical role in development of B-cell malignancies, and the central role of Bruton's tyrosine kinase (BTK) activation in this pathway provides compelling rationale for BTK inhibition as a therapeutic strategy for these conditions. Covalent BTK inhibitors (BTKi) have transformed the treatment landscape of B-cell malignancies, but adverse events and treatment resistance have emerged as therapeutic challenges, with the majority of patients eventually discontinuing treatment due to toxicity or disease progression. Non-covalent BTKi have alternative mechanisms of binding to BTK than covalent BTKi, and therefore offer a therapeutic alternative for patients with B-cell malignancies, including those who have been intolerant to, or experienced disease progression during treatment with a covalent BTKi. Here, we summarise the clinical data, adverse events and mechanisms of resistance observed with covalent BTKi and describe the emerging data for non-covalent BTKi as a novel treatment for B-cell malignancies.

Keywords: B-cell malignancies; B-cell receptor; BTK inhibitors; Bruton’s tyrosine kinase; non-covalent.

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Conflict of interest statement

K.L.L.: consulting/advisory/honoraria—Roche, AstraZeneca, Janssen; C.Y.C.: consulting/advisory/honoraria—Roche, Janssen, MSD, Gilead, Ascentage Pharma, Beigene, AstraZeneca, Loxo/Lilly, TG therapeutics; research funding—Celgene, Roche, AbbVie, MSD; travel expenses—Roche Janssen, AstraZeneca, MSD, Beigene, Loxo/Lilly and TG therapeutics have covalent or non-covalent BTKi commercially available or in development.

Figures

Figure 1
Figure 1
B-cell receptor (BCR) complex-covalent and non-covalent BTKi mechanism of action.
See this image and copyright information in PMC

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