AZ 628 / AstraZeneca - LARVOL DELTA

Exploration of crucial stromal risk genes associated with prognostic significance and chemotherapeutic opportunities in invasive ductal breast carcinoma. (PubMed, J Genet Eng Biotechnol) - "Exploring essential prognostic-risk genes and their association with the prognosis, diagnostic efficacy, and risk-group prediction may provide substantial clues for targeting the breast cancer stromal key-risk genes."

Journal • Breast Cancer • Oncology • Solid Tumor • ADAM8 • CD86 • IGFBP6 • MMP11

Prognosis and immunotherapeutic implications of molecular classification of cervical cancer based on immunophenoscore-related genes. (PubMed, J Biomol Struct Dyn) - "cluster2 had higher immune cell infiltration levels and better prognosis, with greater sensitivity to Cyclopamine, Imatinib, MG-13, Paclitaxel, PHA-665752, Rapamycin, Sorafenib, Sunitinib, and VX-680. In contrast, cluster3 had higher TTN and PIK3CA mutations and greater sensitivity to AZ628, Dasatinib, Doxorubicin, HG-6-64-1, JQ12, Midostaurin, PF-562271, TAE684, and WH-4-023. In conclusion, we developed a feasible risk score model based on IPS-related genes for cervical cancer prognosis and identified potential drugs for different cervical cancer subtypes."

IO biomarker • Journal • Cervical Cancer • Oncology • Solid Tumor • PD-L2 • PIK3CA

BRAF-Mutated Melanoma Cell Lines Develop Distinct Molecular Signatures After Prolonged Exposure to AZ628 or Dabrafenib: Potential Benefits of the Antiretroviral Treatments Cabotegravir or Doravirine on BRAF-Inhibitor-Resistant Cells. (PubMed, Int J Mol Sci) - "Doravirine was particularly effective in reactivating apoptosis and reducing cell growth in highly proliferative resistant cells by increasing tumor-suppressor proteins p16Ink4a and p27Kip1. These findings suggest that antiretroviral drugs can influence apoptosis and cell proliferation in RAF-inhibitor-resistant melanoma cells, offering potential therapeutic strategies for overcoming drug resistance."

Journal • Preclinical • Eye Cancer • Melanoma • Oncology • Retinal Disorders • Solid Tumor • BRAF • CDKN2A

Pan-cancer analysis of oncogenic role of CEP55 and experiment validation in clear cell renal cell carcinoma. (PubMed, Sci Rep) - "We also used Gene Set Cancer Analysis (GSCA) to predict a serious of small molecule CEP55 targeted drugs, such as AZ628, SB52334, SB590885, A-770,041, AZD7762, Elesclomol, panobinostat, BRD-A94377914, and LRRK2-IN-1. Our study indicated that CEP55 overexpression in most caner types was associated with poor prognosis. Notably, CEP55 was closely relevant to immune cell infiltration and impacted the response to immunotherapy and small molecule drugs against cancers."

IO biomarker • Journal • Pan tumor • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CCNA2 • CD4 • CDK1 • CEP55 • KIF11 • LRRK2 • PCNA

Evaluation of the combined antiproliferative effects of Pan-RAF Inhibitor AZ-628 and MEK1 Inhibitor AZD-6244 across a diverse range of tumor cell lines (EORTC-NCI-AACR 2024) - "Our observations of broad synergistic activity of the two compounds suggests that MEK/Raf inhibitor co-treatment could be beneficial for a broader range of cancer types."

Preclinical • Tumor cell • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Solid Tumor • BRAF

Multi-omics profiling combined with molecular docking reveals immune-inflammatory proteins as potential drug targets in colorectal cancer. (PubMed, Biochem Biophys Res Commun) - "Drug prediction, coupled with in vitro experiments, suggests that AZ-628 may act as a potential drug to inhibit the proliferation and migration of CRC cell lines HCT-116 and HT-29 by regulating the aforementioned key biological pathways or proteins...This metabolic shift may reflect an adaptive response in cancer cells, favoring specific amino acids to support their growth. Together, these integrated results provide valuable insights into the intricate landscape of tumor development, highlighting the crossroads of immune regulation, cellular structure, and metabolic reprogramming in the tumorigenic process and providing valuable insights into cancer pathology."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Identification of a Macrophage marker gene signature to evaluate immune infiltration and therapeutic response in hepatocellular carcinoma. (PubMed, Heliyon) - "Moreover, a low-Macrosig score indicates increased sensitivity to AZD.2281, A.443654, ABT.263, ABT.888, AG.014699 and ATRA, while a high Macrosig score indicates increased sensitivity to AZD6482, AKT inhibitor VIII, AS601245, AZ628, AZD.0530 and AZD6244. A novel scoring system was constructed to guide more effective prognostic evaluation and tailoring therapeutic regimens for HCC patients."

Gene Signature • IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • LAG3 • PD-1 • TIGIT

DNA hypomethylation patterns and their impact on the tumor microenvironment in colorectal cancer. (PubMed, Cell Oncol (Dordr)) - "This study unveils a novel epigenetic phenotype in CRC linked to resistance against immune checkpoint inhibitors, presenting a significant step toward personalized medicine by suggesting epigenetic classifications as a means to identify ideal candidates for immunotherapy in CRC. Our findings also highlight potential therapeutic agents for the DMP subtype, offering new avenues for tailored CRC treatment strategies."

Biomarker • IO biomarker • Journal • Tumor microenvironment • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

RAS/RAF/MEK mutated high-grade serous ovarian cancer susceptible to Raf inhibition in vitro but not in vivo (SGO 2024) - "Non-selective (sorafenib, AZ628) and selective (GW5074, dabrafenib) RAFi were added in serial concentrations to each cell line and incubated for 48-96 hours. cBioPortal data mining identified a HGSOC subpopulation hypothesized to be uniquely susceptible to RAFi. The RAS/RAF/MEK pathway phenotype in this subpopulation was replicated in the human derived OV-90 cell line. While non-selective RAFi demonstrate in vitro antitumor activity, a paradoxical effect was observed in vivo, with accelerated tumor growth in the treated arms."

Preclinical • Melanoma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRAF • KRAS

Integrative Analysis of Machine Learning and Molecule Docking Simulations for Ischemic Stroke Diagnosis and Therapy. (PubMed, Molecules) - "AZ_628, which screened from CMap analysis, was found to have lower binding energy with Mmp12, Lgals3, Fam20c, Capg, Pkm2, Sdc4, and Itga5 in microglia subcluster 2 and maybe a therapeutic agent for the poor development of microglia subcluster 2 after stroke. Our study presents a nomogram model for stroke diagnosis and provides a potential molecule agent for stroke therapy."

Journal • Machine learning • Cardiovascular • Ischemic stroke • ITGA5 • LGALS3 • PKM • SDC4

Immune activity score to assess the prognosis, immunotherapy and chemotherapy response in gastric cancer and experimental validation. (PubMed, PeerJ) - "In addition, resistance to Erlotinib, Rapamycin, MG-132, Cyclopamine, AZ628, and Sorafenib was reduced in patients with low IAS. For GC patients, IAS showed excellent robustness in predicting GC prognosis, immune activity status, immunotherapy response, and chemotherapeutic drug resistance. Our study provided novel insights into the prognostic assessment in GC."

IO biomarker • Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CTLA4 • NPC2 • SLC2A3

A novel prognostic N-methylguanosine-related long non-coding RNA signature in clear cell renal cell carcinoma. (PubMed, Sci Rep) - "High-risk group of patients was more susceptible to A.443654, A.770041, ABT.888, AMG.706, and AZ628. Quantitative real-time polymerase chain reaction (qRT-PCR) exhibited that the expression levels of LINC01507, AC093278.2 were very high in all five ccRCC cell lines, AC084876.1 was upregulated in all ccRCC cell lines except 786-O, and the levels of AL118508.1 and DUXAP8 were upregulated in the Caki-1 cell line. This risk model may be promising for the clinical prediction of prognosis and immunotherapeutic responses in patients with ccRCC."

IO biomarker • Journal • Tumor mutational burden • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • DUXAP8 • TMB

Identification of Macrophage Associated Gene Landscape to Evaluate Immune Infiltration and Therapeutic Response in Hepatocellular Carcinoma (APPLE 2023) - "A novel scoring system based on macrophage subclusters was constructed, thereby guiding more effective prognostic evaluation and tailored potential drug agents strategies of HCC patients."

IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Oncology • Solid Tumor • LAG3 • PD-1 • TIGIT

Design, synthesis and characterisation of a novel type II B-RAF paradox breaker inhibitor. (PubMed, Eur J Med Chem) - "ATP competitive type I B-Raf inhibitors, such as vemurafenib (1) and PLX4720 (4) efficiently block the MAPK pathways in B-Raf mutant cells, however these inhibitors induce conformational changes in the wild type B-Raf (B-Raf) kinase domain leading to heterodimerization with C-Raf, causing paradoxical hyperactivation of the MAPK pathway. This unwanted activation may be avoided by another class of inhibitors (type II) which bind the kinase in the DFG-out conformation, such as AZ628 (3) preventing heterodimerization...We discovered that the inhibitor was active and selective for B-Raf, binds in a DFG-out/αC-helix-in conformation, and did not induce the aforementioned paradoxical hyperactivation in the MAPK pathway. We propose that this merging approach can be used to design a novel class of B-Raf inhibitors for translational studies."

Journal • Oncology • BRAF

Comprehensive genomics analysis of aging related gene signature to predict the prognosis and drug resistance of colon adenocarcinoma. (PubMed, Front Pharmacol) - "Low risk patients were more sensitive to small molecule drugs including Erlotinib, Sunitinib, MG-132, CGP-082996, AZ628, Sorafenib, VX-680, and Z-LLNle-CHO. Four risk genes (CALB1, CPA3, NOXA1, and TNNT1) had significant positive correlation with their methylation level, while six genes (CCL22, GPRC5B, HSPA1A, MFNG, PABPC1L, and PCOLCE2) were negatively correlated with their methylation level. This study provides novel understanding of heterogeneity in COAD from the perspective of senescence, and develops signatures for prognosis prediction in COAD."

Gene Signature • IO biomarker • Journal • Tumor mutational burden • Colon Cancer • Colorectal Adenocarcinoma • Gastrointestinal Cancer • Oncology • CALB1 • CCL2 • CCL22 • CPA3 • HSPA1A • PABPC1L • TMB

Prognosis and Characterization of Microenvironment in Cervical Cancer Influenced by Fatty Acid Metabolism-Related Genes. (PubMed, J Oncol) - "Finally, the prediction of therapy targets revealed that the patients with high risk might be sensitive to the RAF inhibitor AZ628. Our findings provide a novel insight for personalized treatment in CC."

Journal • Cervical Cancer • Oncology • Solid Tumor • CD8

Integrative Transcriptomic Analysis Identify Potential m6A Pathway-Related Drugs That Inhibit Cancer Cell Proliferation. (PubMed, Genes (Basel)) - "Both drugs can significantly reduce the cellular level of m6A modification. These results suggest an m6A-related new target pathway by AZ628 and R428 and provide new candidate m6A-related drugs that inhibit cancer cell proliferation."

Journal • Breast Cancer • Melanoma • Oncology • Solid Tumor

Construction and Characterization of n6-Methyladenosine-Related lncRNA Prognostic Signature and Immune Cell Infiltration in Kidney Renal Clear Cell Carcinoma. (PubMed, J Oncol) - "Moreover, high-risk patients may benefit more from AZ628. In conclusion, prognosis prediction of patients with KIRC and new insights for immunotherapy are provided by the m6A-related lncRNA prognostic signature."

IO biomarker • Journal • Clear Cell Renal Cell Carcinoma • Oncology • Renal Cell Carcinoma • Solid Tumor • CD8 • PD-L1 • SNHG1

AZ-628 delays osteoarthritis progression via inhibiting the TNF-α-induced chondrocyte necroptosis and regulating osteoclast formation. (PubMed, Int Immunopharmacol) - "Similarly, the in vivo study demonstrated that AZ-628 could inhibit chondrocyte breakdown and lower osteoclast formation and bone resorption, thereby slowing down subchondral bone changes induced by dynamic bone remodeling and reversing the progression of osteoarthritis in mice. The results of this study indicate that AZ-628 could be used to treat OA byinhibiting chondrocyte necroptosis and regulating osteoclast formation."

Journal • Immunology • Inflammation • Oncology • Osteoarthritis • Pain • Rheumatology • RIPK1 • TNFA

Integrative pharmacogenomics revealed three subtypes with different immune landscapes and specific therapeutic responses in lung adenocarcinoma. (PubMed, Comput Struct Biotechnol J) - "Finally, our study provided subtype-guided personalized treatment strategies: Immune checkpoint blockers (ICBs), doxorubicin, tipifarnib, AZ628, and AZD6244 were for S-Ⅰ; Cisplatin, camptothecin, roscovitine, and A.443654 were for S-Ⅱ; Docetaxel, paclitaxel, vinorelbine, and BIBW2992 were for S-III. We provided a novel molecular classification strategy and revealed three pharmacogenomics-based subtypes for LUAD patients, which uncovered potential subtype-related and patient-specific therapeutic strategies."

Biomarker • Journal • Immune Modulation • Inflammation • Inflammatory Arthritis • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Machine Learning Screens Potential Drugs Targeting a Prognostic Gene Signature Associated With Proliferation in Hepatocellular Carcinoma. (PubMed, Front Genet) - "Prediction of immunotherapy suggetsted the IC50s of immune checkpoint inhibitors including A-443654, ABT-888, AG-014699, ATRA, AUY-922, and AZ-628 in the high-risk group were lower than those in the low-risk group, while the IC50s of AMG-706, A-770041, AICAR, AKT inhibitor VIII, Axitinib, and AZD-0530 in the high-risk group were higher than those in the low-risk group. Drug sensitivity analysis indicated that FARSB was positively correlated with Hydroxyurea, Vorinostat, Nelarabine, and Lomustine, while negatively correlated with JNJ-42756493. DHX37 was positively correlated with Raltitrexed, Cytarabine, Cisplatin, Tiotepa, and Triethylene Melamine. YARS was positively correlated with Axitinib, Fluphenazine and Megestrol acetate. NOP58 was positively correlated with Vorinostat and 6-thioguanine... The five-gene signature associated with proliferation can be used for survival prediction and risk stratification for HCC patients. Potential drugs targeting this gene signature..."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor

Glutathione Peroxidase 4 as a Therapeutic Target for Anti-Colorectal Cancer Drug-Tolerant Persister Cells. (PubMed, Front Oncol) - "In this study, we established 5-fluorouracil and AZ628-tolerant persister cell models in two colorectal cancer cell lines, namely HCT116 and SW620, and revealed the characteristics of colorectal cancer persister cells by cell viability assay and flow cytometry. We investigated the efficacy and mechanism of ferroptosis inducers RSL3 and FIN56 on persister cells, which are glutathione peroxidase 4 inhibitors...Our work reveals that the upregulated glutathione peroxidase 4 and ferrous iron in anti-colorectal cancer drug-tolerant persister cells were potential therapeutic targets. Glutathione peroxidase 4 inhibition combined with chemotherapy or targeted therapy may be a promising therapy for colorectal cancer."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • GPX4

Identification of Fatty Acid Metabolism-Related lncRNAs as Biomarkers for Clinical Prognosis and Immunotherapy Response in Patients With Lung Adenocarcinoma. (PubMed, Front Genet) - "We found that A.443654, AUY922, AZ628, A.770041, AZD.0530, AMG.706, and AG.014699 were more effective in high-risk patients. We constructed a 7-lncRNA prognostic model to predict the OS of patients with LUAD. In addition, the predictive nomogram model based on our established seven fatty acid metabolism-related lncRNA signatures provides better clinical value than that of the traditional TNM staging system in predicting the prognosis of patients with LUAD and presents new insights for personalized treatment."

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

Characterization of KRas pathway inhibitors in 2D and 3D screening formats (AACR 2022) - "On these platforms, we have compared inhibitors targeting the KRas/Raf/MEK pathway via either KRas:SOS interaction (e.g. BI3406), the KRas mutation at G12C (e.g. AMG510), or Raf-kinase (e.g. AZ628) and MEK1/2-kinase activity (e.g. AZD6244). For selected conditions, we addressed this topic by analyzing the inhibitor impact on 3D spheroid growth after shorter incubation times. Our results show that 3D growth analysis either in the soft agar or spheroid setting clearly supports the development of KRas/Raf/MEK pathway inhibitors."

Oncology • KRAS • MAP2K1

Ferroptosis Activation Scoring Model Assists in Chemotherapeutic Agents' Selection and Mediates Cross-Talk With Immunocytes in Malignant Glioblastoma. (PubMed, Front Immunol) - "Critically, potential drugs target to high scoring samples are predicted, namely, SNX2112, AZ628, and bortezomib and five compounds from the CellMiner database. Taken together, ferroptosis associates with glioblastoma aggressiveness, cross-talk with immunocytes and offer novel chemotherapy strategy."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor