TY - JOUR
T1 - Review of the development of BTK inhibitors in overcoming the clinical limitations of ibrutinib
AU - Ran, Fansheng
AU - Liu, Yun
AU - Wang, Chen
AU - Xu, Zhongyuan
AU - Zhang, Yanan
AU - Liu, Yang
AU - Zhao, Guisen
AU - Ling, Yong
N1 - Funding Information:
Anti-apoptotic BCL-2 family proteins are overexpressed in B-cell lymphoma and have recently emerged as a promising target to treat B-cell lymphoma. Venetoclax is the first orally active BCL-2 inhibitor, approved by the FDA for the treatment of CLL and SLL. BCL-2 upregulation has been found in ABC-DLBCL patients with poorer response to ibrutinib therapy [95]. Chronic ibrutinib exposure results in reprogramming of resistant cells to express high levels of BCL-2, while decreases anti-apoptotic proteins BCL-XL and MCL-1 levels, implying that it has the potential to overcome the venetoclax resistance caused by increased BCL-XL and MCL-1 levels [96–98]. Therefore, the combination of ibrutinib and venetoclax represents a rational approach. Synergistic effects of this drug combination have also been found in multiple CLL, DLBCL and FL cell lines, as well as ibrutinib-resistant cells generated by either genetic mutation or drug treatment [95,99]. A phase 2 study (NCT02756897) evaluated the efficacy of ibrutinib in combination with venetoclax as first-line therapy in high-risk elderly patients with CLL [100]. After 12 cycles of treatment, the complete response (CR) rate was 88%, and the undetectable minimal residual disease was achieved in 61% of patients. The AEs profile was similar to that reported with two drugs monotherapy, with no new safety signals emerging. In addition, several clinical trials (NCT03513562, NCT03943342, NCT04477486, NCT02956382, and NCT04273139) are currently underway to investigate the combination of ibrutinib and venetoclax for the treatment of ibrutinib-resistant CLL, R/R MCL, R/R FL and WM. Although still at an early stage, these studies showed convincingly positive outcomes, including high CR and well-tolerated [101,102], supporting ibrutinib and venetoclax combination as a promising therapeutic strategy for the treatment of B-cell malignancies including those that are ibrutinib and/or venetoclax resistant.This work was supported by the Key R&D Program of Jiangsu Province (BE2021677), Key Natural Science Foundation of Jiangsu Higher Education Institutions (20KJA350002), China Postdoctoral Science Foundation (2018T110533), and Applied Research Projects of Nantong City (MS12020047).
Funding Information:
This work was supported by the Key R&D Program of Jiangsu Province ( BE2021677 ), Key Natural Science Foundation of Jiangsu Higher Education Institutions ( 20KJA350002 ), China Postdoctoral Science Foundation ( 2018T110533 ), and Applied Research Projects of Nantong City ( MS12020047 ).
Publisher Copyright:
© 2021 Elsevier Masson SAS
PY - 2022/2/5
Y1 - 2022/2/5
N2 - Bruton's tyrosine kinase (BTK) regulates multiple important signaling pathways and plays a key role in the proliferation, survival, and differentiation of B-lineage cells and myeloid cells. BTK is a promising target for the treatment of hematologic malignancies. Ibrutinib, the first-generation BTK inhibitor, was approved to treat several B-cell malignancies. Despite the remarkable potency and efficacy of ibrutinib against various lymphomas and leukemias in the clinics, there are also some clinical limitations, such as off-target toxicities and primary/acquired drug resistance. As strategies to overcome these challenges, second- and third-generation BTK inhibitors, BTK-PROTACs, as well as combination therapies have been explored. In this review, we summarize clinical developments of the first-, second- and third-generation BTK inhibitors, as well as recent advances in BTK-PROTACs and ibrutinib-based combination therapies.
AB - Bruton's tyrosine kinase (BTK) regulates multiple important signaling pathways and plays a key role in the proliferation, survival, and differentiation of B-lineage cells and myeloid cells. BTK is a promising target for the treatment of hematologic malignancies. Ibrutinib, the first-generation BTK inhibitor, was approved to treat several B-cell malignancies. Despite the remarkable potency and efficacy of ibrutinib against various lymphomas and leukemias in the clinics, there are also some clinical limitations, such as off-target toxicities and primary/acquired drug resistance. As strategies to overcome these challenges, second- and third-generation BTK inhibitors, BTK-PROTACs, as well as combination therapies have been explored. In this review, we summarize clinical developments of the first-, second- and third-generation BTK inhibitors, as well as recent advances in BTK-PROTACs and ibrutinib-based combination therapies.
KW - Bruton's tyrosine kinase (BTK) inhibitors
KW - Combination therapy
KW - Drug resistance
KW - Ibrutinib
KW - Off-target toxicities
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U2 - 10.1016/j.ejmech.2021.114009
DO - 10.1016/j.ejmech.2021.114009
M3 - Review article
C2 - 34839996
AN - SCOPUS:85120166085
SN - 0223-5234
VL - 229
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 114009
ER -