Design and synthesis of novel 1-substituted 3-(6-phenoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine analogs as selective BTK inhibitors for the treatment of mantle cell lymphoma

2020 ◽  
Vol 94 ◽  
pp. 103367 ◽  
Author(s):  
Fansheng Ran ◽  
Yang Liu ◽  
Shengping Yu ◽  
Kaiwen Guo ◽  
Wendi Tang ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Design And Synthesis ◽  
Mantle Cell ◽  
Btk Inhibitors

scholarly journals Design And Synthesis Of Novel Pyrazolopyrimidine-Based Derivatives As Reversible BTK Inhibitors With Potent Antiproliferative Activity In Mantle Cell Lymphoma

2021 ◽  
Author(s):  
Fansheng Ran ◽  
Yang Liu ◽  
Guisen Zhao
Keyword(s):  
Mantle Cell Lymphoma ◽  
Antiproliferative Activity ◽  
Antitumor Agents ◽  
Cell Lymphoma ◽  
Dependent Manner ◽  
Single Digit ◽  
Apoptotic Pathway ◽  
Design And Synthesis ◽  
Mantle Cell ◽  
Btk Inhibitors

Abstract Development of Bruton’s tyrosine kinase (BTK) inhibitors is of great value and significance in the treatment of B-cell malignancies and autoimmune diseases. Herein, a novel class of pyrazolopyrimidine-based BTK inhibitors were designed and evaluated in mantle cell lymphoma (MCL) cell lines. We demonstrated that target compounds had made great progress in improvement of antiproliferative activity compared to lead compound. Compounds 13c, 13g, 13h, 13l, 13n and 13o demonstrated effectively antiproliferative activity in MCL cells lines with single-digit micromolar potency. Furthermore, compound 13l specifically disturbed mitochondrial membrane potential and increased reactive oxygen species level in Z138 cells in a dose-dependent manner. 13l induced cell apoptosis through the caspase 3- mediated apoptotic pathway in Z138 cells. Overall, this study provides valuable lead compounds for developing antitumor agents.

BTK Inhibitors Differentially Induce Apoptosis but Similarly Suppress Chemotaxis and Lipid Accumulation in Mantle Cell Lymphoma

2020 ◽  
Author(s):  
Zhuojun Liu ◽  
Jia Liu ◽  
Tainming Zhang ◽  
Lin Li ◽  
Shuo Zhang ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
Stimulated Raman Scattering ◽  
Biological Effects ◽  
Immunoblot Analysis ◽  
Mantle Cell ◽  
Apoptotic Genes ◽  
Btk Inhibitors ◽  
Cell Chemotaxis

Abstract Background: The more selective second-generation BTK inhibitors (BTKis) Acalabrutinib and Zanubrutinib and the first-generation BTK inhibitor (BTKi) Ibrutinib are highlighted by their clinical effectiveness in mantle cell lymphoma (MCL), however, similarities and differences of their biological and molecular effects on anti-survival of MCL cells induced by these BTKis with distinct binding selectivity against BTK remain largely unknown. Methods: AlamarBlue assays were performed to define cytotoxicity of BTKis against MCL cells, Jeko-1 and Mino. Cleaved PARP and caspase-3 levels were examined by immunoblot analysis to study BTKi-induced apoptotic effects. Biological effects of BTKis on MCL-cell chemotaxis and lipid droplet (LD) accumulation were examined in Jeko-1, Mino and primary MCL cells via Transwell and Stimulated Raman scattering imaging analysis respectively. Enzyme-linked immunoassays were used to determine CCL3 and CCL4 levels in MCL-cell culture supernatants. RNA-seq analyses identified BTKi targets which were validated by quantitative RT-PCR (qRT-PCR) and immunoblot analysis. Results: Acalabrutinib and Zanubrutinib induced moderate apoptosis in Ibrutinib high-sensitive JeKo-1 cells and Ibrutinib low-sensitive Mino cells, which was accompanied by cleaved PARP and caspase-3. Such effects might be caused by the stronger ability of Ibrutinib to upregulate the expression of pro-apoptotic genes, such as HRK, GADD45A , and ATM , in JeKo-1 cells than in Mino cells, and the expression of such apoptotic genes was slightly changed by Acalabrutinib and Zanubrutinib in both JeKo-1 and Mino cells. Further, Acalabrutinib, Zanubrutinib and Ibrutinib reduced MCL-cell chemotaxis with similar efficiency, due to their similar abilities to downmodulate chemokines, such as CCL3 and CCL4. Also, these three BTKis similarly suppressed MCL-cell LD accumulation via downregulating lipogenic factors, DGAT2, SCD, ENPP2 and ACACA without significant differences. Conclusion: BTKis demonstrated differential capacities to induce MCL-cell apoptosis due to their distinct capabilities to regulate the expression of apoptosis-related genes, and similar biological and molecular inhibitory effects on MCL-cell chemotaxis and LD accumulation.

Distinct BTK inhibitors differentially induce apoptosis but similarly suppress chemotaxis and lipid accumulation in mantle cell lymphoma

2021 ◽  
Author(s):  
Zhuojun Liu ◽  
Jia Liu ◽  
Tainming Zhang ◽  
Lin Li ◽  
Shuo Zhang ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
Stimulated Raman Scattering ◽  
Biological Effects ◽  
Immunoblot Analysis ◽  
Mantle Cell ◽  
Apoptotic Genes ◽  
Btk Inhibitors ◽  
Cell Chemotaxis

Abstract Background: The more selective second-generation BTK inhibitors (BTKi) Acalabrutinib and Zanubrutinib and the first-generation BTKi Ibrutinib are highlighted by their clinical effectiveness in mantle cell lymphoma (MCL), however, similarities and differences of their biological and molecular effects on anti-survival of MCL cells induced by these BTKi with distinct binding selectivity against BTK remain largely unknown.Methods: AlamarBlue assays were performed to define cytotoxicity of BTKi against MCL cells, Jeko-1 and Mino. Cleaved PARP and caspase-3 levels were examined by immunoblot analysis to study BTKi-induced apoptotic effects. Biological effects of BTKi on MCL-cell chemotaxis and lipid droplet (LD) accumulation were examined in Jeko-1, Mino and primary MCL cells via Transwell and Stimulated Raman scattering imaging analysis respectively. Enzyme-linked immunoassays were used to determine CCL3 and CCL4 levels in MCL-cell culture supernatants. RNA-seq analyses identified BTKi targets which were validated by quantitative RT-PCR (qRT-PCR) and immunoblot analysis.Results: Acalabrutinib and Zanubrutinib induced moderate apoptosis in Ibrutinib high-sensitive JeKo-1 cells and Ibrutinib low-sensitive Mino cells, which was accompanied by cleaved PARP and caspase-3. Such effects might be caused by the stronger ability of Ibrutinib to upregulate the expression of pro-apoptotic genes, such as HRK, GADD45A, and ATM, in JeKo-1 cells than in Mino cells, and the expression of such apoptotic genes was slightly changed by Acalabrutinib and Zanubrutinib in both JeKo-1 and Mino cells. Further, Acalabrutinib, Zanubrutinib and Ibrutinib reduced MCL-cell chemotaxis with similar efficiency, due to their similar abilities to downmodulate chemokines, such as CCL3 and CCL4. Also, these three BTKi similarly suppressed MCL-cell LD accumulation via downregulating lipogenic factors, DGAT2, SCD, ENPP2 and ACACA without significant differences. Conclusion: BTKi demonstrated differential capacities to induce MCL-cell apoptosis due to their distinct capabilities to regulate the expression of apoptosis-related genes, and similar biological and molecular inhibitory effects on MCL-cell chemotaxis and LD accumulation.

Comparative Efficacy of First-Line Regimens in Relapsed/Refractory Mantle Cell Lymphoma (MCL): A Proportional Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-33
Author(s):  
Philip A Haddad ◽  
Dalia Hammoud ◽  
Kevin M. Gallagher
Keyword(s):  
Mantle Cell Lymphoma ◽  
English Language ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Meta Analysis ◽  
The Elderly ◽  
First Line ◽  
Mantle Cell ◽  
Duration Of Response ◽  
Btk Inhibitors

Introduction: Mantle cell lymphoma (MCL) is an incurable B-cell malignancy that disproportionately affects the elderly. After first-line therapy failure, relapsed/refractory MCL assumes a more aggressive and universally fatal course. Currently, several classes of chemo/biologic therapies are approved in the second line. However, these agents and their combinations have not been compared head-to-head. We conducted this proportional meta-analysis to evaluate their relative impact on selected clinical outcomes. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of relapsed/refractory MCL; trials that explored the efficacy of first-line approved antineoplastic agents and their combinations that comprised: BTK-inhibitors (Ibrutininb (IB), Acalabrutinib, Zanubrutinib), Bortezomib (Velcade, VEL), Venetoclax (VEN), Lenalidomide (LEN), and Bendamustine+Rituximab (B-R); and studies reporting types of responses and duration of response. Proportional meta-analysis was conducted using random-effects model. The respective 95% confidence intervals were calculated, and funnel plots were constructed. Results: Thirteen studies comprising a total of 1,264 participants were included. The pooled overall response rates, ORR (95%CI), of the regimens were: 74% (66,81) BTK-inhibitors, 39% (25,53) VEL, 34% (24,46) LEN, 85% (78,92) B-R, 75% (58,92) VEN-IB, and 88% (79,97) IB-R. The pooled complete responses, CR (95%CI), of the regimens were: 33% (20,47) BTK-inhibitors, 9% (5,13) VEL, 6% (4,9) LEN, 45% (36,54) B-R, 42% (22,63) VEN-IB, and 44% (30,58) IB-R. There were no significant differences in ORR and CR between BTK-inhibitors, B-R, VEN-IB, and IB-R. ORR of VEL and LEN also did not significantly differ. However, ORR and CR of the former group were significantly higher than those of the latter. The pooled partial responses, PR (95%CI), of the regimens were: 41% (32,50) BTK-inhibitors, 28% (20,38) VEL, 28% (15,43) LEN, 41% (35,47) B-R, 34% (15,53) VEN-IB, and 44% (30,58) IB-R. There were no significant differences between PR of the regimens. The weighted duration of responses in months, DOR (95%CI), of the regimens were: 20 BTK-inhibitors, 9 VEL, 16 LEN, and 20 B-R. Conclusions: This proportional meta-analysis is the first to compare the current regimens in first-line relapsed/refractory MCL. It indicates that BTK-inhibitors monotherapy, IB combinations with R or VEN, and B-R provide equivalent ORR and CR rates that are significantly better than VEL and LEN with notably longer duration of response. It also raises questions about whether there is an additional ORR and CR benefits when adding VEN or R to IB in this clinical setting. Disclosures No relevant conflicts of interest to declare.

scholarly journals Differential effects of BTK inhibitors ibrutinib and zanubrutinib on NK-cell effector function in patients with mantle cell lymphoma

Haematologica ◽  
2019 ◽  
Vol 105 (2) ◽  
pp. e76-e79 ◽  
Author(s):  
Thijs W.H. Flinsenberg ◽  
Charnelle C. Tromedjo ◽  
Nan Hu ◽  
Ye Liu ◽  
Yin Guo ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Effector Function ◽  
Differential Effects ◽  
Mantle Cell ◽  
Btk Inhibitors ◽  
Cell Effector Function ◽  
Cell Effector

scholarly journals Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma

2019 ◽  
Vol 26 (2) ◽  
Author(s):  
C. Owen ◽  
N. L. Berinstein ◽  
A. Christofides ◽  
L. H. Sehn
Keyword(s):  
Tyrosine Kinase ◽  
Mantle Cell Lymphoma ◽  
First Generation ◽  
Kinase Inhibitors ◽  
Cell Lymphoma ◽  
Comparable Efficacy ◽  
Non Hodgkin Lymphoma ◽  
Mantle Cell ◽  
Bruton Tyrosine Kinase ◽  
Btk Inhibitors

Mantle cell lymphoma (mcl) is a rare subtype of aggressive B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. Patients typically require multiple lines of therapy, and those with relapsed or refractory (r/r) disease have a very poor prognosis. The Bruton tyrosine kinase (btk) inhibitor ibrutinib has proven to be an effective agent for patients with r/r mcl. Although usually well tolerated, ibrutinib can be associated with unique toxicities, requiring discontinuation in some patients. Effective and well-tolerated alternatives to ibrutinib for patients with r/r mcl are therefore needed. Novel btk inhibitors such as acalabrutinib, zanubrutinib, and tirabrutinib are designed to improve on the safety and efficacy of first-generation btk inhibitors such as ibrutinib. Data from single-arm clinical trials suggest that, compared with ibrutinib, second-generation btk inhibitors have comparable efficacy and might have a more favourable toxicity profile. Those newer btk inhibitors might therefore provide a viable treatment option for patients with r/r mcl.

scholarly journals Distinct BTK inhibitors differentially induce apoptosis but similarly suppress chemotaxis and lipid accumulation in mantle cell lymphoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhuojun Liu ◽  
Jia Liu ◽  
Tianming Zhang ◽  
Lin Li ◽  
Shuo Zhang ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
Stimulated Raman Scattering ◽  
Biological Effects ◽  
Immunoblot Analysis ◽  
Mantle Cell ◽  
Apoptotic Genes ◽  
Btk Inhibitors ◽  
Cell Chemotaxis

Abstract Background The more selective second-generation BTK inhibitors (BTKi) Acalabrutinib and Zanubrutinib and the first-generation BTKi Ibrutinib are highlighted by their clinical effectiveness in mantle cell lymphoma (MCL), however, similarities and differences of their biological and molecular effects on anti-survival of MCL cells induced by these BTKi with distinct binding selectivity against BTK remain largely unknown. Methods AlamarBlue assays were performed to define cytotoxicity of BTKi against MCL cells, Jeko-1 and Mino. Cleaved PARP and caspase-3 levels were examined by immunoblot analysis to study BTKi-induced apoptotic effects. Biological effects of BTKi on MCL-cell chemotaxis and lipid droplet (LD) accumulation were examined in Jeko-1, Mino and primary MCL cells via Transwell and Stimulated Raman scattering imaging analysis respectively. Enzyme-linked immunoassays were used to determine CCL3 and CCL4 levels in MCL-cell culture supernatants. RNA-seq analyses identified BTKi targets which were validated by quantitative RT-PCR (qRT-PCR) and immunoblot analysis. Results Acalabrutinib and Zanubrutinib induced moderate apoptosis in Ibrutinib high-sensitive JeKo-1 cells and Ibrutinib low-sensitive Mino cells, which was accompanied by cleaved PARP and caspase-3. Such effects might be caused by the stronger ability of Ibrutinib to upregulate the expression of pro-apoptotic genes, such as HRK, GADD45A, and ATM, in JeKo-1 cells than in Mino cells, and the expression of such apoptotic genes was slightly changed by Acalabrutinib and Zanubrutinib in both JeKo-1 and Mino cells. Further, Acalabrutinib, Zanubrutinib and Ibrutinib reduced MCL-cell chemotaxis with similar efficiency, due to their similar abilities to downmodulate chemokines, such as CCL3 and CCL4. Also, these three BTKi similarly suppressed MCL-cell LD accumulation via downregulating lipogenic factors, DGAT2, SCD, ENPP2 and ACACA without significant differences. Conclusion BTKi demonstrated differential capacities to induce MCL-cell apoptosis due to their distinct capabilities to regulate the expression of apoptosis-related genes, and similar biological and molecular inhibitory effects on MCL-cell chemotaxis and LD accumulation.

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