Targeting Bruton's tyrosine kinase for the treatment of B cell associated malignancies and autoimmune diseases: Preclinical and clinical developments of small molecule inhibitors

Abstract

B cell receptor (BCR) signaling plays a key role in B cell development and function. Aberrant BCR signaling has been confirmed as a central driver for the pathogenesis of various B cell malignancies. Bruton's tyrosine kinase (BTK) is a vital component of BCR signaling and exhibits overexpression in various B cell leukemias and lymphomas. Inhibiting BTK has been proved as an efficient way for B cell malignancy intervention. Remarkable achievements have been made in the pursuit of selective BTK inhibitors, represented by the success of the irreversible BTK inhibitors, ibrutinib and acalabrutinib. Constantly emerging agents exhibiting superior efficacy and safety in preclinical and clinical studies provide promising therapeutics for the treatment of B cell malignancies.

Discovery and biological evaluation of N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-2-oxo-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide as potent Bruton’s tyrosine kinase inhibitors

“…We then investigated the antiproliferative activity of compound 2 in TMD8 lymphoma cells, which express high levels of BTK and are widely used to evaluate the antitumor effect of BTK inhibitors [ 18 , 30 – 32 ]. Ibrutinib and ACP-196 were used as the positive control compounds [ 22 , 33 , 34 ]. The results revealed that compound 2 inhibited the proliferation of TMD8 cells with an IC 50 value of 0.028 μM, indicating that compound 2 was slightly less potent than ibrutinib (IC 50 = 0.010 μM) and ACP-196 (IC 50 = 0.014 μM) (Table 2 ).…”

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

“…Bruton's tyrosine kinase (BTK) is expressed on B lymphocytes, from pre‐B‐cell to mature B‐cell stages . BTK functions as an important regulator in B‐cell development and as a component of BCR signalling . BTK also promotes mast cell degranulation and cytokine production upon FcεRI cross‐linking .…”

“…BTK inhibition leads to derangements in BCR‐mediated B‐cell pathways, inhibition of neutrophil migration, FcεR‐induced cytokine release from monocytes and macrophages and FcγR‐induced mast cell degranulation . Small molecule BTK inhibitors have been FDA approved for the treatment of mantle cell lymphoma and chronic lymphoblastic leukaemia …”

“…112 BTK functions as an important regulator in Bcell development and as a component of BCR signalling. 113 BTK also promotes mast cell degranulation and cytokine production upon FceRI cross-linking. 114 Mutations in BTK are implicated in X-linked agammaglobulinemia type 1, an immunodeficiency associated with a lack of mature B lymphocytes and failure of immunoglobulin (Ig) heavy chain rearrangement.…”

“…116 Small molecule BTK inhibitors have been FDA approved for the treatment of mantle cell lymphoma and chronic lymphoblastic leukaemia. 113 Oral PRN1008, a covalent reversible BTK inhibitor, is currently in phase 3 testing for efficacy in moderate-to-severe pemphigus (NCT03762265). Phase 1 results suggested that the compound is safe and tolerable, while phase 2 showed promising efficacy with greater than 50% of patients achieving disease control within 4 weeks of treatment initiation.…”