Optimization of a novel piperazinone series as potent selective peripheral covalent BTK inhibitors

Author(s):  
Bin Ma ◽  
Claire M. Metrick ◽  
Chungang Gu ◽  
Marc Hoemberger ◽  
Bekim Bajrami ◽  
...  
Keyword(s):  
2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Brooke Benner ◽  
William E. Carson

AbstractBruton’s tyrosine kinase (BTK) inhibitors, drugs utilized in cancer, are being repurposed for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (COVID-19). Recently, BTK inhibitors acalabrutinib and ibrutinib have been found to protect against pulmonary injury in a small group of patients infected with SARS-CoV-2. The high levels of pro-inflammatory cytokines found in the circulation of COVID-19 patients with severe lung disease suggest the involvement of the innate immune system in this process. Understanding the potential mechanism of action of BTK inhibition in SARS-CoV-2 is clearly of importance to determine how acalabrutinib, ibrutinib and possibly other BTK inhibitors may provide protection against lung injury.


2021 ◽  
pp. 116223
Author(s):  
John P Guilinger ◽  
Archna Archna ◽  
Martin Augustin ◽  
Andreas Bergmann ◽  
Paolo A Centrella ◽  
...  
Keyword(s):  

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3150
Author(s):  
Irene López-Oreja ◽  
Heribert Playa-Albinyana ◽  
Fabián Arenas ◽  
Mónica López-Guerra ◽  
Dolors Colomer

Chronic lymphocytic leukemia (CLL) is characterized by a high degree of genetic variability and interpatient heterogeneity. In the last decade, novel alterations have been described. Some of them impact on the prognosis and evolution of patients. The approval of BTK inhibitors, PI3K inhibitors and Bcl-2 inhibitors has drastically changed the treatment of patients with CLL. The effect of these new targeted therapies has been widely analyzed in TP53-mutated cases, but few data exist about the response of patients carrying other recurrent mutations. In this review, we describe the biological pathways recurrently altered in CLL that might have an impact on the response to these new therapies together with the possibility to use new actionable targets to optimize treatment responses.


eJHaem ◽  
2021 ◽  
Author(s):  
Bibian M.E. Tullemans ◽  
Mieke F.A. Karel ◽  
Valentine Léopold ◽  
Marieke S. ten Brink ◽  
Constance C.F.M.J. Baaten ◽  
...  

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Danling Gu ◽  
Hanning Tang ◽  
Jiazhu Wu ◽  
Jianyong Li ◽  
Yi Miao

AbstractB cell receptor (BCR) signaling is involved in the pathogenesis of B cell malignancies. Activation of BCR signaling promotes the survival and proliferation of malignant B cells. Bruton tyrosine kinase (BTK) is a key component of BCR signaling, establishing BTK as an important therapeutic target. Several covalent BTK inhibitors have shown remarkable efficacy in the treatment of B cell malignancies, especially chronic lymphocytic leukemia. However, acquired resistance to covalent BTK inhibitors is not rare in B cell malignancies. A major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481)  mutations, which disrupt the binding of covalent BTK inhibitors. Additionally, adverse events due to the off-target inhibition of kinases other than BTK by covalent inhibitors are common. Alternative therapeutic options are needed if acquired resistance or intolerable adverse events occur. Non-covalent BTK inhibitors do not bind to C481, therefore providing a potentially effective option to patients with B cell malignancies, including those who have developed resistance to covalent BTK inhibitors. Preliminary clinical studies have suggested that non-covalent BTK inhibitors are effective and well-tolerated. In this review, we discussed the rationale for the use of non-covalent BTK inhibitors and the preclinical and clinical studies of non-covalent BTK inhibitors in B cell malignancies.


2020 ◽  
Vol 94 ◽  
pp. 103361
Author(s):  
Jeanluc Bertrand ◽  
Hana Dostálová ◽  
Vladimir Krystof ◽  
Radek Jorda ◽  
Alejandro Castro ◽  
...  

2017 ◽  
Vol 27 (16) ◽  
pp. 3939-3943 ◽  
Author(s):  
Sobhana Babu Boga ◽  
Abdul-Basit Alhassan ◽  
Jian Liu ◽  
Deodial Guiadeen ◽  
Arto Krikorian ◽  
...  

2021 ◽  
pp. 108816
Author(s):  
Michael Stack ◽  
Keith Sacco ◽  
Riccardo Castagnoli ◽  
Alicia A. Livinski ◽  
Luigi D. Notarangelo ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document