TAK‐632 / Takeda - LARVOL DELTA

The efficacy of NST-628, a non-degrading pan-RAF/MEK molecular glue, and MEK inhibitors for overcoming acquired osimertinib resistance mediated by TRIM24-BRAF fusions in EGFR mutant NSCLC (AACR 2025) - "Next, we utilized a panel of compounds targeting the RAS/RAF/MAPK pathway including agents targeting pan-RAS (RMC-6236 and RMC-7977), SHP2 (RMC-4550), BRAF (dabrafenib, encorafenib, tovorafenib and vemurafenib), pan-RAF (TAK-632), MEK (binimetinib, cobimetinib, selumetinib and trametinib), pan-RAF/MEK (NST-628) and assessed whether targeting signal transduction molecule downstream of EGFR could overcome this adaptative resistance mechanism. TRIM24-BRAF expressing cells showed minimal sensitivity to BRAF, SHP2 or RAS targeting single agents. Taken together, our findings indicate that expression of TRIM24-BRAF fusion induce osimertinib resistance in EGFR mutant NSCLC and targeting the MEK pathway using trametinib or NST-628 can overcome osimertinib resistance in this setting."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • EGFR • TRIM24

Prognostic signature based on S100 calcium-binding protein family members for lung adenocarcinoma and its clinical significance. (PubMed, Comput Methods Biomech Biomed Engin) - "Finally, small molecular compounds targeting prognostic genes were screened using CellMiner database, and molecular docking confirmed the binding of AMG-176, Estramustine, and TAK-632 with prognostic genes. In conclusion, we generated a prognostic signature with robust and reliable predictive ability, which may provide guidance for prognosis and treatment of LUAD."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Construction of luciferase-expressing Neospora caninum and drug screening. (PubMed, Parasit Vectors) - "In conclusion, a luciferase-expressing N. caninum strain was successfully constructed, which provides an effective tool for drug screening and related research on N. caninum. In addition, TAK-632 was found to inhibit the growth of N. caninum, which could be considered as a candidate lead compound for new therapeutics for neosporosis."

Journal • CNS Disorders • Fibrosarcoma • Oncology • Sarcoma • Solid Tumor

Combination of conformation-specific RAF inhibitors synergise to inhibit MAPK signalling in Pancreatic Ductal Adenocarcinoma cell lines. (EACR-AACR 2024) - "Material and Methods We first characterized a panel of 3 cell lines (PSN1, PANC1 and Capan2) in term of sensitivity to MAPK inhibitors (RAFi CO/DI: Vemurafenib and Encorafenib; RAFi CI/DO: Sorafenib and TAK-632; or MEKi: Trametinib and Cobimetinib) using dose-response assay for pERK and viability; but also, in term of RAS signalling protein level using Western blot and whole cell proteomic. Finally, we observed that Encorafenib+TAK-632 and Vemurafenib+Sorafenib combinations efficiently synergise to inhibit MAPK signalling in the 3 cell lines although the synergy for cell growth inhibition was associated with cell line specific RAS dependency. Conclusion Those results suggest that a combination of RAFi could be a good strategy to inhibit MAPK-mediated cell proliferation in the context of PDAC."

Preclinical • Gastrointestinal Cancer • Melanoma • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • EGFR • KRAS

Identification of tyrphostin AG879 and A9 inhibiting replication of chikungunya virus by screening of a kinase inhibitor library. (PubMed, Virology) - "High-throughput screening of 419 kinase inhibitors was performed based on the cytopathic effect method, and six kinase inhibitors with reduced cytopathic effects, including tyrphostin AG879 (AG879), tyrphostin 9 (A9), sorafenib, sorafenib tosylate, regorafenib, and TAK-632, were identified. The time-of-addition and time-of-removal assays illustrated that both AG879 and A9 function in the middle stage of CHIKV life cycle. Further, AG879 and A9 do not affect viral attachment; however, they inhibit viral RNA replication, and exhibit antiviral activity against CHIKV Eastern/Central/South African and Asian strains, Ross River virus and Sindbis virus in vitro."

Journal • Chikungunya • Infectious Disease

Effect of heat-reinforcing needling on the inflammation and necrotizing apoptosis of synovial cells in synovial tissues of knee joint in rabbits with cold syndrome rheumatoid arthritis (PubMed, Zhen Ci Yan Jiu) - "HRN can reduce synovial inflammation of knee joint in rabbits with cold syndrome RA, which may be related to its function in inhibiting the necrotizing apoptosis of synovial cells."

Journal • Preclinical • Immunology • Inflammation • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • IL1B • IL6 • RIPK1 • TNFA

The pan-RAF inhibitor tovorafenib suppresses NF1-mutant glioma through upregulation of FOXO1 and triggering of oncogene-induced senescence (AACR 2023) - "In addition to tovorafenib, we also tested TAK632, a tool compound that targets RAF and has a different structure . We are currently planning to test tovorafenib against orthotopic xenografts of NF1 mutant glioma compared to BRAFV600E mutant glioma. Our data suggest that tovorafenib may act differently in NF1 mutant cells compared to BRAFV600E mutant cells."

Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • BRAF • CDKN1A • FOXO1 • NF1

Clinicopathological Implication and Immunotherapy Response Predictive Potential of T cell Exhaustion Signature in Triple Negative Breast Cancer: a Machine Learning Case (USCAP 2023) - "A Tex signature might be helpful in predicting the immunotherapy response and immune phenotype of cancer patients."

Clinical • IO biomarker • Machine learning • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • CD8 • HAVCR2 • KLRG1 • LAG3 • PD-1 • TIGIT

Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy. (PubMed, Acta Pharm Sin B) - "Our group previously identified TAK-632 (5) as an effective necroptosis inhibitor by dual-targeting RIP1 and RIP3...Especially, it was able to exhibit remarkable anti-inflammatory treatment efficacy in a DSS-induced mouse model of UC. Taken together, the highly potent, selective, orally active anti-necroptosis inhibitor represents promising candidate for clinical treatment of UC."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Systemic Inflammatory Response Syndrome • Ulcerative Colitis • RIPK1 • TNFA

[VIRTUAL] DAY101, a potent pan-RAF inhibitor with activity in preclinical models harboring MAPK pathway alterations beyond BRAF V600E mutation (AACR 2021) - "Accordingly, the tool compound TAK-632, which exhibits comparable biochemical and cellular potency to DAY101, was used alternatively as needed for in vitro assays.Single-agent anti-proliferative activity was observed in a melanoma BRAF fusion PDX model treated with TAK-632 ex vivo, with less sensitivity observed in models beyond melanoma harboring other BRAF fusions. Inhibition of both RAF monomers and dimers by DAY101 enables a broader indication selection strategy, beyond LGG and BRAF alterations. Ongoing translational work will highlight the potential utility of DAY101 in adult tumors harboring RAS or RAF alterations, both as a single agent and in hypothesis-driven combinations."

Preclinical • Astrocytoma • Glioma • Melanoma • Oncology • Solid Tumor • BRAF • KIAA1549 • KRAS

N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy) benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK-632) Analogues as Novel Necroptosis Inhibitors by Targeting Receptor-Interacting Protein Kinase 3 (RIPK3): Synthesis, Structure-Activity Relationships and In Vivo Efficacy. (PubMed, J Med Chem) - "Moreover, it showed favorable and drug-like pharmacokinetic properties in rats with an oral bioavailability of 25.2%. Thus, these RIPK3-targeting small molecules represent promising lead structures for further development."

Journal • Preclinical • Immunology • Systemic Inflammatory Response Syndrome