MRT67307 / University of Dundee, Dana-Farber Cancer Institute - LARVOL DELTA

Autophagy Inhibition Prevents CAR-T Exhaustion and Terminal Differentiation Via TCF7 Accumulation (ASH 2023) - "To explore whether autophagy inhibitors could prevent CAR-T cell exhaustion triggered by antigen-independent CAR tonic signaling, we applied 3 autophagy inhibitors: SBI0206965, MRT67307, Compound C, respectively, to the culture medium of CD19.4-1BBz CAR-T cells. We found that all the 3 autophagy inhibitors could reduce CAR-T cell exhaustion and terminal differentiation. The results were replicable with GD2.28z CAR-T cells."

Hematological Malignancies • Leukemia • Oncology • TCF7

Serum amyloid P component suppresses porcine epidemic diarrhea virus replication through TLR4-mediated IFN-β signaling pathway. (PubMed, Vet Microbiol) - "By using TBK1/IKBKE inhibitor MRT67307 in PEDV-infected cells, the antiviral activity of SAP was inhibited...Moreover, the interaction between SAP and PEDV N protein and the functional domain of SAP were investigated. From the results of this study, it can be concluded that the interaction between SAP and PEDV N protein activates the TLR4-mediated IFN signaling pathway, thereby inhibiting PEDV replication."

IO biomarker • Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • IFNB1 • IKBKE • TLR4

STING inhibition enables efficient plasmid-based gene expression in primary vascular cells: A simple and cost-effective transfection protocol. (PubMed, PLoS One) - "MRT67307 and BX795 also improved plasmid expression in human and rat aortic SMCs. In conclusion, this study presents a modification enabling efficient plasmid transfection in primary vascular ECs and SMCs, offering a favorable approach to studying protein function(s) in these cell types, with potential implications for other primary cell types that are challenging to transfect."

Cost effectiveness • HEOR • Journal • CYB5A • NOS3 • STING

Ginsenoside Rg5 enhances the radiosensitivity of lung adenocarcinoma via reducing HSP90-CDC37 interaction and promoting client protein degradation. (PubMed, J Pharm Anal) - "Ginsenoside Rg5 or MRT67307 (an IKKε/TBK1 inhibitor) pretreatment suppressed irradiation-induced elevation of the LC3-II/β ratio and restored irradiation-induced downregulation of p62 expression...In conclusion, ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma. It interacts with HSP90α and reduces the binding between HSP90 and CDC37, thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CDK4 • HSP90AA1

Ginsenoside Rg5 Enhances Radiosensitivity of Lung Adenocarcinoma via Reducing HSP90 CDC37 Interaction and Promoting Client Protein Degradation (ASTRO 2023) - "Ginsenoside Rg5 or MRT67307 pre-treatment suppressed irradiation-induced elevation of the LC3-II/ß ratio and restored irradiation-induced downregulation of p62 expression... ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma. It interacts with HSP90 and reduces the binding between HSP90 and CDC37, thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CDK4 • HSP90AA1 • RAF1

Ginsenoside Rg5's Enhancement of Radiosensitivity of Lung Adenocarcinoma via Reducing HSP90 CDC37 Interaction and Promoting Client Protein Degradation. (PubMed, Int J Radiat Oncol Biol Phys) - "ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma. It interacts with HSP90 and reduces the binding between HSP90 and CDC37, thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CDK4 • HSP90AA1 • RAF1

Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection. (PubMed, Nat Commun) - "Treatment with idronoxil, or the small molecule inhibitor MRT67307, suppresses TBK1/IKKε signalling and attenuates cellular and molecular lung inflammation in SARS-CoV-2-challenged mice. Our findings additionally demonstrate that engagement of STING is not the major driver of these inflammatory responses and establish a critical role for TBK1/IKKε signalling in SARS-CoV-2 hyper-inflammation."

Journal • Preclinical • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • STING

Application of deep generative model for design of Pyrrolo[2,3-d] pyrimidine derivatives as new selective TANK binding kinase 1 (TBK1) inhibitors. (PubMed, Eur J Med Chem) - "Further medicinal chemistry optimization campaign led to the discovery of the most potent compound 7l, which exhibited strong enzymatic inhibitory activity against TBK1 with an IC value of 22.4 nM 7l had a superior inhibitory activity in human monocytic THP1-Blue cells reporter gene assay than MRT67307. Furthermore, 7l significantly inhibited TBK1 downstream target genes cxcl10 and ifnβ expression in THP1 and RAW264.7 cells induced by poly (I:C) and lipopolysaccharide, respectively. This study suggested that combination of deep conditional transformer neural network SyntaLinker and transfer learning could be a powerful tool for scaffold hopping in drug discovery."

Journal • CXCL10 • GLI2 • IFNB1

Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection. (PubMed, Int J Mol Sci) - "The best-in-class IKKis, targeting TBK-1 (MRT67307) and IKKβ (TCPA-1) respectively, were also able to significantly induce viral reactivation in CD4+ T cells from people living with HIV (PLWH) ex vivo...Finally, as expected, IKKis did not upregulate cell activation markers in primary lymphocytes and innate immune signaling was blocked, resulting in downregulation of inflammatory cytokines. Overall, our results support a dual role of IKKis as immune modulators being able to tackle the HIV latent reservoir in lymphoid and myeloid cellular models and putatively control the hyperinflammatory responses in chronic HIV-1 infection."

Journal • Human Immunodeficiency Virus • Immune Modulation • Immunology • Infectious Disease • Inflammation • CD4

TBK1 inhibitors enhance transfection efficiency by suppressing p62/SQSTM1 phosphorylation. (PubMed, Genes Cells) - "Transfection efficiency was enhanced when cells were treated with one of the following TBK1 inhibitors, BX795, MRT67307, or amlexanox. This effect was synergistically improved when the two inhibitors were used in combination. Our results indicate that TBK1 inhibitors enhanced transfection efficiency by suppressing p62 phosphorylation."

Journal • SQSTM1

Therapeutic targeting of TANK-binding kinase signaling towards anticancer drug development: Challenges and opportunities. (PubMed, Int J Biol Macromol) - "This review further highlighted the therapeutic potential of potent and selective TBK1 inhibitors, including Amlexanox, Compound II, BX795, MRT67307, SR8185 AZ13102909, CYT387, GSK8612, BAY985, and Domainex. These inhibitors may be implicated to facilitate therapeutic management of cancer and TBK1-associated diseases in the future."

Journal • Review • Oncology

[VIRTUAL] UVB-irradiated Keratinocyte-derived Extracellular Vesicles Induced Proinflammatory Responses in Macrophages (ACR-CONVERGENCE 2021) - "TBK1 inhibitor MRT67307 also showed a similar effect (12.6±0.71 vs. 304.6±94.4 pg/mL P0.05)... KEV-UVB were mediators of inflammation, and triggered both STING and inflammasome-mediated cytokine release. Targeting the STING signaling pathway may provide insight into a potential therapeutic approach for UVB-induced skin inflammation."

Dermatitis • Immunology • Inflammation • CD63 • CD9 • IL1B • STING

Transient blockade of TBK1/IKKε allows efficient transduction of primary human natural killer cells with vesicular stomatitis virus G-pseudotyped lentiviral vectors. (PubMed, Cytotherapy) - "The authors demonstrate that inhibition of TBK1/IKKε enables the reliable generation of genetically modified NK cells using VSV-G LVs. The authors' protocol can be readily adapted to generate clinical-grade NK cells and thus has the potential to facilitate the clinical evaluation of genetically modified NK cell-based therapeutics in the future."

Journal • Immune Modulation • Inflammation • Oncology • CD19 • HER-2

Exploring the stability of inhibitor binding to SIK2 using molecular dynamics simulation and binding free energy calculation. (PubMed, Phys Chem Chem Phys) - "In this work, we studied the detailed interactions between SIK2 and four of its inhibitors, HG-9-91-01, KIN112, MRT67307, and MRT199665, using molecular docking, molecular dynamics simulation, binding free energy calculation, and interaction fingerprint analysis...The key residues involved in binding with SIK2 are conserved among all four inhibitors. Our results explain the detailed interaction of SIK2 with its inhibitors at the molecular level, thus paving the way for the development of targeted efficient anti-cancer drugs."

Journal • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor

[VIRTUAL] UVB-irradiated keratinocytes-derived extracellular vesicles: Mediator of proinflammatory responses in macrophages (SID 2021) - "TBK1 inhibitor MRT67307 also showed similar effect (12.6±0.71 vs. 304.6±94.4 pg/mL P <0.05). KEV-UVB were mediators of inflammation, and triggered STING-mediated cytokine release. Targeting the STING signaling pathway may provide insight into a potential therapeutic approach for UVB-induced skin inflammation."

Dermatitis • Inflammation • CASP3 • STING

DNA damage-triggered activation of cGAS-STING pathway induces apoptosis in human keratinocyte HaCaT cells. (PubMed, Mol Immunol) - "Treatment with MRT67307, an inhibitor of TBK1-IRF3-IFNβ pathway, blocked UVB-induced apoptosis. Therefore, we conclude that NF-κB pathway and IFNβ pathway residing in the downstream of STING are resposible for apoptosis of UVB-irradiated or cisplatin-treated HaCaT cells."

Journal • Immunology • Inflammation • STING

[VIRTUAL] Spirulina Stimulates Inflammatory Cytokine Production Through the STING and TLR Pathways in Dermatomyositis in Vitro (ACR-ARHP 2020) - "PBMCs were also pre-treated for 1 hour with the following inhibitors: STING inhibitor, H-151; TLR4 inhibitor, TAK 242; TLR2 and TLR4 inhibitor, Sparstolonin B; and TBK1 inhibitor, MRT67307. Our preliminary results show that Spirulina increases production of key inflammatory cytokines TNFα and IFNβ. For TNFα production, Spirulina’s immunostimulatory effects appear to be primarily mediated via the TLR4 pathway. Inhibition of TBK1, an important kinase in the innate immune system active in both the STING and NF-kappa B pathways, also significantly decreases TNFα production."

Preclinical • Dermatology • Dermatomyositis • Immunology • Myositis • STING • TNFA

[VIRTUAL] Plasma-derived Extracellular Vesicles Induced STING-mediated Proinflammatory Effects in Dermatomyositis (ACR-ARHP 2020) - "Besides, TBK1 inhibitors Amlexanox and MRT67307 also suppressed DM patients’ plasma derived EVs-induced IFNb release by inhibiting TBK1 phosphorylation. EVs derived from plasma trigger STING-mediated proinflammatory effects in DM. The STING signaling pathway is activated during EVs triggering of proinflammatory effects and was at least partially mediated by dsDNA captured by EVs. Targeting STING pathway might provide insight into a potential therapeutic approach for DM."

Dermatitis • Dermatology • Dermatomyositis • Immunology • Inflammation • Myositis • IL6 • STING • TNFA