Recent development of BTK-based dual inhibitors in the treatment of cancers

Ran, Fansheng; Liu, Yun; Xu, Zhongyuan; Meng, Chunyan; Yang, Dezhi; Qian, Jianqiang; Deng, Xuexian; Zhang, Yanan; Ling, Yong

doi:10.1016/j.ejmech.2022.114232

Cited by 15 publications

(6 citation statements)

References 115 publications

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“…A feature of IB and other BTK inhibitors is that they regulate, to varying degrees and either directly or indirectly, the activity of multiple additional kinases such as SYK, FLT3, JAK, PI3K that affect other downstream pathways. Inhibition of these other pathways may be the basis for the activity of BTK inhibitors in non-malignant immunological disorders [22][23][24]. On the basis of its established ability to inhibit malignant B cells, IB was selected as the comparator as, in in vitro screens, LUX also inhibits recombinant wild type and C481S mutant BTK at 8.4-27 nM and 2.5-13.1 nM [25].…”

Section: Introductionmentioning

confidence: 99%

Luxeptinib interferes with LYN-mediated activation of SYK and modulates BCR signaling in lymphoma

2023

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Luxeptinib (LUX) is a novel oral kinase inhibitor that inhibits FLT3 and also interferes with signaling from the BCR and cell surface TLRs, as well as activation of the NLRP3 inflammasome. Ongoing clinical trials are testing its activity in patients with lymphoma and AML. This study sought to refine understanding of how LUX modulates the earliest steps downstream of the BCR following its activation by anti-IgM in lymphoma cells in comparison to ibrutinib (IB). LUX decreased anti-IgM-induced phosphorylation of BTK at Y551 and Y223 but its ability to reduce phosphorylation of kinases further upstream suggests that BTK is not the primary target. LUX was more effective than IB at reducing both steady state and anti-IgM-induced phosphorylation of LYN and SYK. LUX decreased phosphorylation of SYK (Y525/Y526) and BLNK (Y96) which are necessary regulators of BTK activation. Further upstream, LUX blunted the anti-IgM-induced phosphorylation of LYN (Y397) whose activation is required for phosphorylation of SYK and BLNK. These results indicate that LUX is targeting autophosphorylation of LYN or a step further upstream of LYN in the cascade of signal generated by BCR and that it does so more effectively than IB. The fact that LUX has activity at or upstream of LYN is important because LYN is an essential signaling intermediate in multiple cellular signaling processes that regulate growth, differentiation, apoptosis, immunoregulation, migration and EMT in normal and cancer cells.

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Section: Introductionmentioning

confidence: 99%

Luxeptinib interferes with LYN-mediated activation of SYK and modulates BCR signaling in lymphoma

2023

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Section: Introductionmentioning

confidence: 99%

“…Single inhibition of EZH2 or G9a has shown some efficacy in various tumour models (17) and the EZH2 inhibitor (EZH2i) tazemetostat is FDA-approved for treatment of follicular lymphoma and epithelioid sarcoma (17). However, epigenetic inhibitors have yet to demonstrate clinical efficacy in most solid tumours (17). Single inhibition approaches may be limited by physical interaction between the two complexes, and the existence of epigenetic redundancy, such as G9a placing the EZH2-canonical H3K27me3 mark (17).…”

Section: Introductionmentioning

confidence: 99%

“…However, epigenetic inhibitors have yet to demonstrate clinical efficacy in most solid tumours (17). Single inhibition approaches may be limited by physical interaction between the two complexes, and the existence of epigenetic redundancy, such as G9a placing the EZH2-canonical H3K27me3 mark (17). Genetic knock-down and pharmacological inhibition of both methyltransferases has been shown to have greater biological effect than inhibition of either alone and is required for maximal tumour growth inhibition (18), and for induction of apoptosis via IL24 (11).…”

Section: Introductionmentioning

confidence: 99%

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cMYC-mediated immune repression is reversed by inhibition of H3K9/H3K27 methylation maintenance

Dye,

Laing,

Garner

et al. 2023

Preprint

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Aberrant cMYC activity is a key driver of cancer, involved in several hallmark processes. Alongside the canonical hallmark of proliferation, cMYC represses immune signalling in a cell-intrinsic manner. The histone methyltransferases EZH2 and G9a interact with cMYC to modulate gene expression, including repression of immune genes via H3K27 and H3K9 histone methylation. Analyses of 565 cell lines derived from solid cancers demonstrated that greater cMYC-G9a/EZH2-mediated repression correlates with lower immune gene scores in a cell-intrinsic manner (innate, Type I and Type II IFN response), an effect most evident in MYC-amplified cell lines. In ovarian high-grade serous carcinoma (HGSC) cell lines and an in vivo murine model of HGSC, HKMTi-1-005, an inhibitor of H3K27/H3K9 methylation maintenance, relieved cMYC-G9a/EZH2 repression whilst inducing an immune response. A 7-gene immune signature (7ISG), related to viral mimicry signalling, is at the core of the HGSC immune response to HKMTi-1-005. In MYC-amplified HGSC patients, a low 7ISG score was associated with poor survival. Additionally, MYC-amplified cell lines were significantly more sensitive to HKMTi-1-005, whilst a low 7ISG score was associated with greater HKMTi-1-005 sensitivity, effects that were independent of canonical cMYC transcriptional activation. Examining the effects of HKMTi-1-005 treatment in a MYC-deregulated lung adenocarcinoma (LuAd) revealed induction of an immune response in vitro and prolonged survival in vivo. This suggests that inhibition of H3K27/H3K9 methylation maintenance will have efficacy in cMYC-deregulated tumours with low 7ISG scores, via disruption of cMYC-mediated repression of cell autonomous immune signalling and induction of an anti-tumour immune response.

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“…BTK inhibition has been demonstrated as a practical way to treat hematologic tumors such as mantle cell lymphoma (MCL), chronic lymphocytic leukemia, and Waldenstrom macroglobulinemia. Some covalent or noncovalent BTK inhibitors, including ibrutinib, zanubrutinib, and orelabrutinib (Figure ), have been approved. − However, substantial limitations have been encountered in the inhibitors, especially the development of drug resistance and toxicity. For example, the first covalent BTK inhibitor, ibrutinib, acquired resistance caused by the BTK C481S mutant .…”

Section: Introductionmentioning

confidence: 99%

Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton’s Tyrosine Kinase for the Treatment of Lymphoma

et al. 2022

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Bruton's tyrosine kinase proteolysis-targeting chimeras (BTK-PROTACs) have emerged as a promising approach to address the limitations of BTK inhibitors. However, conducting the rational discovery of orally bioavailable BTK-PROTACs presents significant challenges. In this study, dimensionality reduction analysis and model molecule validation were utilized to identify some key structural features for improving the oral absorption of BTK-PROTACs. The results were applied to optimize the newly discovered BTK-PROTACs B1 and B2. Compound C13 was discovered with improved oral bioavailability, high BTK degradation activity, and selectivity. It exhibited inhibitory effects against different hematologic cancer cells and attenuated the BTK-related signaling pathway. The oral administration of C13 effectively reduced BTK protein levels and suppressed tumor growth. This study led to the discovery of a new orally bioavailable BTK-PROTAC for the treatment of lymphoma, and we hope that the strategy will find wide utility.

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Recent development of BTK-based dual inhibitors in the treatment of cancers

Cited by 15 publications

References 115 publications

Luxeptinib interferes with LYN-mediated activation of SYK and modulates BCR signaling in lymphoma

Luxeptinib interferes with LYN-mediated activation of SYK and modulates BCR signaling in lymphoma

cMYC-mediated immune repression is reversed by inhibition of H3K9/H3K27 methylation maintenance

Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton’s Tyrosine Kinase for the Treatment of Lymphoma

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