TAE-684 / Novartis, Scripps Research Institute - LARVOL DELTA

Common Regulatory Mechanisms Mediated by Cuproptosis Genes in Inflammatory Bowel Disease and Major Depressive Disorder. (PubMed, Genes (Basel)) - "These findings have substantially enhanced our understanding of the similarities and differences in the regulatory mechanisms of CRGs within brain-gut axis diseases. Key biomarkers have been identified, and potential therapeutic drugs have been predicted to effectively target IBD and MDD."

Journal • CNS Disorders • Depression • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Major Depressive Disorder • Mood Disorders • Psychiatry • CDKN2A • DLAT • LIAS • SLC31A1

Identification of Systemic Drug Targets for Anti-cavernous Fibrosis in the Treatment of Erectile Dysfunction, Guided by Genome-Wide Mendelian Randomization. (PubMed, Am J Mens Health) - "Drug predictions utilizing DSigDB identified nolone phenylpropionate, sorafenib, and NVP-TAE684 as significantly associated with TGFBR2. Through MR and colocalization analyses, the present study identified five potential drug targets for ED, with TGFBR2 showing remarkable relevance in blood. These findings offer valuable insights and potential leads for the development of more effective ED therapies, which may also contribute to cutting down the expenses involved in drug development."

Journal • Erectile Dysfunction • Fibrosis • Immunology • ABCB4 • ABCC6 • EGF • SMAD3 • TGFBR2

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

Identification of miRNA signature in cancer-associated fibroblast to predict recurrent prostate cancer. (PubMed, Comput Biol Med) - "Our findings conducted an integrated bioinformatic analysis to develop a CAFs-related miRNAs model that provides prognostic insights into individualized and precise treatment for prostate adenocarcinoma patients. Downregulation of miR-106b-5p in CAFs significantly suppressed tumor growth, suggesting a potential therapeutic target for cancer treatment."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CAFs • MIR106B • MIR133B • MIR145 • MIR15B • MIR191 • MIR222 • MIR96

Lysophosphatidic Acid Stimulates Mitogenic Activity and Signaling in Human Neuroblastoma Cells through a Crosstalk with Anaplastic Lymphoma Kinase. (PubMed, Biomolecules) - "These effects were curtailed by the selective ALK inhibitors NPV-TAE684 and alectinib. LPA enhanced the inhibitory phosphorylation of the tumor suppressor FoxO3a, and this response was impaired by the ALK inhibitors. These results indicate that LPA stimulates mitogenesis of human neuroblastoma cells through a crosstalk with ALK."

Journal • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • ALK • ALKAL2 • NTRK

IL27 and IL1RN are causally associated with acute pancreatitis: a Mendelian randomization study. (PubMed, Aging (Albany NY)) - "IL1RN was identified as a risk factor for acute pancreatitis (AP), but IL27 was found to be a protective factor for AP."

Journal • Pancreatitis • IL1R2 • IL1RN

Identification and validation of m6A-associated ferroptosis genes in renal clear cell carcinoma. (PubMed, Cell Biol Int) - "NIACIN, TAE-684, ROCILETINIB, and others treat ccRCC. We found ccRCC prognostic genes that work. This discovery may lead to new ccRCC treatments."

IO biomarker • Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CHAC1 • EGFR • NNMT • TRIB3

Discovery of a doublecortin-like kinase 1 inhibitor to prevent inflammatory responses in acute lung injury. (PubMed, Bioorg Chem) - "In this study, we designed and synthesized a series of NVP-TAE684-based derivatives as novel anti-inflammatory agents targeting DCLK1...Furthermore, compound a24 showed in vivo anti-inflammatory activity in an LPS-challenged acute lung injury model. These findings suggest that compound a24 may serve as a novel candidate for the development of DCLK1 inhibitors and a potential therapeutic agent for the treatment of inflammatory diseases."

Journal • Acute Lung Injury • Inflammation • Oncology • Respiratory Diseases

A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance. (PubMed, Acta Pharm Sin B) - "Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models...A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine."

Journal • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

Drug repurposing analysis for colorectal cancer through network medicine framework: Novel candidate drugs and small molecules. (PubMed, Cancer Invest) - "Based on the gene module, polyethylene glycol, gallic acid, pyrazole, cordycepin, phenothiazine, pantoprazole, cysteamine, indisulam, valinomycin, trametinib, BRD-K81473043, AZD8055, dovitinib, BRD-A17065207, and tyrphostin AG1478 presented as drugs and small molecule candidates previously studied in the CRC. Lornoxicam, suxamethonium, oprelvekin, sirukumab, levetiracetam, sulpiride, NVP-TAE684, AS605240, 480743.cdx, HDAC6 inhibitor ISOX, BRD-K03829970, and L-6307 are proposed as novel drugs and small molecule candidates for CRC."

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

Transcriptomic clock predicts vascular changes of prodromal diabetic retinopathy. (PubMed, Sci Rep) - "We also identified NVP-TAE684, geldanamycin, and NVP-AUY922 as the top three potential drugs which can potentially attenuate the early DR. Although we need more in vivo studies in the future to support our re-purposed drugs, we have provided a data-driven approach to drug discovery."

Journal • Diabetes • Diabetic Retinopathy • Metabolic Disorders • Retinal Disorders

Using ChEMBL to Complement Schistosome Drug Discovery. (PubMed, Pharmaceutics) - "Until an effective vaccine is registered for use, the cornerstone of schistosomiasis control remains chemotherapy with praziquantel...Our process identified seven compounds (fimepinostat, trichostatin A, NVP-BEP800, luminespib, epoxomicin, CGP60474 and staurosporine) with ex vivo anti-schistosomula potencies in the sub-micromolar range...ChEMBL toxicity data were also leveraged to provide further support for progressing CGP60474 (as well as luminespib and TAE684) as a novel anti-schistosomal compound. As very few compounds are currently at the advanced stages of the anti-schistosomal pipeline, our approaches highlight a strategy by which new chemical matter can be identified and quickly progressed through preclinical development."

Journal • Infectious Disease

PI3K pathway mutation predicts an activated immune microenvironment and better immunotherapeutic efficacy in head and neck squamous cell carcinoma. (PubMed, World J Surg Oncol) - "The PI3K pathway mutation status could be considered as a potential biomarker to predict better immunotherapeutic efficacy and clinical outcomes after immunotherapy in HNSC patients."

IO biomarker • Journal • Tumor mutational burden • Head and Neck Cancer • Immune Modulation • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • TMB

Solute Carrier Family 7 Member 11 (SLC7A11) is a Potential Prognostic Biomarker in Uterine Corpus Endometrial Carcinoma. (PubMed, Int J Gen Med) - "The half-maximal inhibitory concentration (IC50) results obtained with the cohort from TCGA showed that Z-VAD-FMK (Caspase inhibitor), S-Triphenylmethyl-L-cysteine (S-Trityl-L-cysteine), and TAE684 (ALK inhibitor) had higher IC50 values in low-expression patient (p < 0.05). SLC7A11 overexpression is associated with favorable prognosis of patients with UCEC and is associated with TIICs and the responses to immunotherapy."

Biomarker • IO biomarker • Journal • Cervical Cancer • Endometrial Cancer • Gynecologic Cancers • Immune Modulation • Oncology • Solid Tumor • Uterine Cancer • SLC7A11

Autocrine EGF and TGF-α promote primary and acquired resistance to ALK/c-Met kinase inhibitors in non-small-cell lung cancer. (PubMed, Pharmacol Res Perspect) - "Clinically, NSCLC patients with high expression of EGF and TGF-α developed primary resistance to crizotinib. Furthermore, combined treatment with gefitinib circumvented EGF- and TGF-α-mediated primary and acquired resistance to TAE684/SGX-523. Taken together, these results suggested increased autocrine EGF and TGF-α conferred primary and acquired resistance to ALK/c-Met kinase inhibitors in NSCLC."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET • TGFA

Assessment of alterations in histone modification function and guidance for death risk prediction in cervical cancer patients. (PubMed, Front Genet) - "Patients with high HMAG scores were more suitable for the treatment of CHIR-99021, embelin, FTI-277, JNK-9L, JQ12, midostaurin, PF-562271, pyrimethamine, and thapsigargin, and patients with low HMAG scores were more suitable for the treatment of BMS-536924, CP466722, crizotinib, PHA-665752, rapamycin, and TAE684. We comprehensively evaluated the histone modification status in cervical cancer patients and revealed histone modification-associated prognostic genes to construct the HMAG signature, aiming to provide a new insight into prognosis prediction and precise clinical treatment."

Epigenetic controller • Journal • Cervical Cancer • Oncology • Solid Tumor

Distinct Response of Circulating microRNAs to the Treatment of Pancreatic Cancer Xenografts with FGFR and ALK Kinase Inhibitors. (PubMed, Cancers (Basel)) - "Mice with pancreatic cancer cell (COLO357PL) xenografts were treated with inhibitors of either fibroblast growth factor receptor kinase (FGFR; PD173074) or anaplastic lymphoma kinase receptor (ALK; TAE684)...Distinct signatures that include circulating miR-1 and miR-22 are associated with the efficacy of ALK and FGFR inhibition, respectively. We propose that monitoring changes in circulating miR profiles can provide an early signature of treatment response or resistance to pathway-targeted drugs, and thus provide a non-invasive measurement to rapidly assess the efficacy of candidate therapies."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • ALK • FGFR

Integrative analysis reveals clinically relevant molecular fingerprints in pancreatic cancer. (PubMed, Mol Ther Nucleic Acids) - "Further integrative analysis revealed that temozolomide and NVP-TAE684 showed higher sensitivity in the C1 subgroup, whereas the C2 cell lines were more sensitive to SR1001 and SRT-1720. Our results also showed that PCCLs with mutations in CDKN2A, TP53, and SMAD4 were more sensitive to certain anti-cancer drugs. Our integrative analysis identified molecular features of pancreatic cancer that were associated with clinical significance and drug sensitivity, providing potentially effective strategies for precision treatments of patients with pancreatic cancer."

Clinical • Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD4 • CDKN2A • SMAD4 • TP53

Tumour-derived substrate-adherent cells promote neuroblastoma survival through secreted trophic factors. (PubMed, Mol Oncol) - "In co-culture experiments, S-type cells protected N-type cells from apoptosis induced by the oncogenic ALK inhibitor TAE684...Overall, the tumour-derived S-type cells prevented apoptosis in the N-type cells via ALK-independent STAT3 activation triggered by secreted factors. The inhibition of these factors in combination with ALK inhibition could provide a new direction for targeted therapies to treat high-risk neuroblastoma."

Journal • Immunology • Neuroblastoma • Oncology • Solid Tumor • ALK • POSTN

"#MachineLearning identifies TAE684 and ruxolitinib as top #DrugRepurposing candidates for #Alzheimers disease https://t.co/mzlQgYHQvl Steve Rodriguez, Petar Todorov, Sarah Boswell, Kyle Evans, George Zhou, Nathan Johnson, Bradley Hyman, Peter Sorger, Mark Albers & Artem Sokolov" (@BRAINCURES)

Alzheimer's Disease • CNS Disorders

Anaplastic lymphoma kinase inhibitor NVP‑TAE684 suppresses the proliferation of human pancreatic adenocarcinoma cells. (PubMed, Oncol Rep) - "Furthermore, inhibition of ALK with NVP‑TAE684 or siRNA synergistically enhanced gemcitabine‑induced cell death by inducing apoptosis. In conclusion, the findings of the present study indicated that NVP‑TAE684 exerted its antitumor effects by inducing G2/M arrest and apoptosis via the inhibition of the ALK signaling pathway, and suggests its potential use as an antitumor agent against pancreatic adenocarcinoma."

Journal • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • ALK • CASP3 • CASP7

Binge-Like Ethanol Drinking Activates ALK Signaling and Increases the Expression of STAT3 Target Genes in the Mouse Hippocampus and Prefrontal Cortex. (PubMed, Genes Brain Behav) - "To identify novel ethanol-induced target genes downstream of the ALK and STAT3 pathway, we analyzed the NIH LINCS L1000 database for gene signature overlap between ALK inhibitor (alectinib and NVP-TAE684) and STAT3 inhibitor (niclosamide) treatments on cell lines. We further demonstrated by qPCR that expression of the putative STAT3 genes Nr1h2, Smarcc1, Smarca4, and Gpnmb were increased in either the PFC or HPC after binge-like drinking. Together, these results indicate activation of the ALK-STAT3 signaling pathway in the brain after binge-like ethanol consumption, identify putative novel ethanol-responsive STAT3 target genes, and suggest that STAT3 inhibition may be a potential method to reduce binge drinking in humans."

Journal • Oncology • ALK • GFAP • SMARCA4 • STAT3