Bruton’s Tyrosine Kinase Signaling and Advancement in Multiple Myeloma Therapy
Pp. 131-158 (28)
Max Von Suskil,
Omar S. Al-Odat,
Prachi S. Narayan,
Shantu G Amin
The Bruton’s tyrosine kinase (BTK) is a non-receptor protein-tyrosine
kinase (PTK) required for the growth and differentiation of B-lymphocytes, which play
a critical role in the progression of numerous neoplasms. Therefore, BTK has emerged
as an exciting and attractive target for inhibition of hematological malignancies.
Various BTK inhibitors have already proved remarkable tumor suppressing ability in
clinical studies. Ibrutinib was the trail blazing BTK inhibitor that first showed
exceptional tumor inhibition in patients, this molecule showed excellent response in
refractory/relapsed (R/R) conditions with high-risk genetic lesions patients, particularly
among chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Based
on ibrutinib’s efficacy and tolerability, in 2016, the Food and Drug Administration
(FDA) approved it as a first-line treatment for CLL patients. Ibrutinib occupies the
ATP-binding active site of BTK, making salt bridges within the hinge that connects the
two enzyme lobes followed by the unsaturated acrylamide group of ibrutinib covalently
bonding with the BTK cysteine 481 residue to irreversibly form an inactive adduct.
However, ibrutinib’s irreversible binding mechanism leads to acquired resistance to the
medication. Both resistance arising due to mutations that impair the affinity of ibrutinib
for BTK and the undesirable side effects of the drug have led to the development of
numerous second-generation inhibitors. The efficacy and specificity of novel BTK
inhibiting agents such as Acalabrutinib, ONO/GS-4059, KS99, and other small
molecules have substantiated solutions to ibrutinib’s shortcomings. The detailed role of
BTK signaling pathways, and its cross-talk between other signaling pathways, the
significance of BTK inhibition in hematological malignancies, and the current progress
in the discovery of small molecule BTK inhibitors are presented in this chapter.
Multiple myeloma, Hematological malignancies, Bruton’s tyrosine
kinase, Myeloma stem cells, Drug development.