LY2090314 / Eli Lilly - LARVOL DELTA

Targeting TCF-1 to Potentiate the Functional Capacity of HIV/SIV-Specific CD8+ T Cells (CROI 2025) - "In addition, LY2090314 was able to induce TCF-1 expression in SIV-specific CD8+ T cells of RM on ART. These data support the further evaluation of LY2090314 in SIV-infected RM on ART to determine whether TCF-1 induction can enhance the functional activity of CD8+ T cells and promote durable virologic control."

Human Immunodeficiency Virus • Infectious Disease • CD8 • CTNNB1 • IL7

Insilico targeting of virus entry facilitator NRP1 to block SARS-CoV2 entry. (PubMed, PLoS One) - "Computational modeling of the interaction between the b1 domain of NRP1 and the receptor-binding domain of the spike protein suggested that AZD3839 and LY2090314 could effectively hinder the NRP1-spike interaction. Therefore, these compounds may serve as potential drug candidates to reduce SARS-CoV-2 infectivity."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • NRP1

Targeting β-Catenin Protein Degradation in Refractory B-Cell Malignancies (ASH 2024) - "Background and Significance : Approaches for targeted elimination of B-cells as the root-cause of disease have been highly effective in the treatment of B-cell malignancies (rituximab, ibrutinib)...Most notably, among 4,518 compounds screened, we identified 9 top-ranking compounds that converge on targeting the β-catenin protein degradation pathway : GSK3B-inhibitors (AZD7969, LY2090314, GSK3i IV, CHIR99021, ML320), the neddylation-activating enzyme (NAE)-inhibitor pevonedistat and proteasome inhibitors (MG-132, Bortezomib, Ixazomib) showed high B-cell-selectivity along with known B-cell-selective drugs such as dexamethasone and ibrutinib...Conclusion : This study reveals a previously unrecognized targetable dependency of B-cell malignancies on β-catenin protein degradation that is amenable to near-term evaluation in patients with refractory disease. The discovery of GSK3B-dependent β-catenin protein degradation as unique B-lymphoid vulnerability provides a rationale to..."

B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Targeted Protein Degradation • CTNNB1 • IKZF1 • TCF7

A New Strategy for Adult T-Cell Leukemia Treatment Targeting Glycogen Synthase Kinase-3β. (PubMed, Eur J Haematol) - "GSK-3β functions as an oncogene in ATL and could be a potential therapeutic target."

Journal • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Oncology • BAK1 • BAX • BCL2L1 • BIRC5 • CCNA2 • CDK1 • CDKN1A • GSK3B • JUNB • MCL1 • MYC • NFKBIA • STAT3 • TP53 • XIAP

GSK3 regulation Wnt/β-catenin signaling affects adipogenesis in bovine skeletal muscle fibro/adipogenic progenitors. (PubMed, Int J Biol Macromol) - "LY2090314/XAV-939 was used to activate/inhibit Wnt/β-catenin signal. Furthermore, we found that blocking GSK3 enhanced the paracrine effects of FAPs-MuSCs and increased myotube formation in muscle satellite cells (MuSCs). Overall, our results outline a single-cell atlas of skeletal muscle development in Yanbian cattle, revealed the role of Wnt/GSK3/β-catenin signaling in FAPs adipogenesis, and provide a theoretical basis for further regulation of bovine IMF deposition."

Journal • ITGA7 • ITGB1 • NCAM1 • PPARG

Novel selective inhibitors of macropinocytosis-dependent growth in pancreatic ductal carcinoma. (PubMed, Biomed Pharmacother) - "Four compounds (Ivermectin, Tyrphostin A9, LY2090314, and Pyrvinium Pamoate) selectively hampered nutrient scavenging in KRAS-mutated cancer cells. Their ability to impair albumin-dependent proliferation was replicated both in different 2D cell culture systems and 3D organotypic models. These findings provide a new set of compounds specifically targeting macropinocytosis, which could have therapeutic applications in cancer and infectious diseases."

Journal • Gastrointestinal Cancer • Infectious Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • AVEN • KRAS

Glycogen synthase kinase 3 activity enhances liver inflammation in MASH. (PubMed, JHEP Rep) - "Mice with established MASH resulting from a choline-deficient high-fat diet (CDHFD) or FFC diet were also treated with two structurally distinct GSK3 inhibitors (LY2090314 and elraglusib [9-ING-41]). This study provides preclinical data for the future investigation of GSK3 pharmacological inhibitors in human MASH. The results of this study are important to hepatologists, vascular biologists, and investigators studying the mechanisms of inflammatory liver disease and MASH, as well as those interested in drug development."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • CCL2 • CXCL2 • XCL2

GLYCOGEN SYNTHASE KINASE-3β INHIBITION SUPPRESSES EFFECTOR CD4+ T CELL FUNCTION THROUGH METABOLIC REPROGRAMMING (DDW 2024) - "Methods : We utilized a Seahorse XF analyzer to examine the metabolic state of human Th1 and Th17 cells in real-time in the presence or absence of GSK3α/β inhibitor (LY2090314)... GSK3β inhibition impairs effector CD4 + T cell activity and function in vitro and in vivo , potentially via metabolic reprogramming towards mitochondrial respiration. GSK3β is a metabolic checkpoint associated with T cell-driven inflammation."

Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • CD4 • RAG1

Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts. (PubMed, Cells) - "Finally, LY2090314 caused gene expression dysregulation mainly involving pathways related to transcription regulation, cell proliferation, and chromatin remodeling. For the first time, our work provides the underlying molecular basis for synthetic lethality due to cohesin mutations and suggests that targeting the WNT may be a promising therapeutic approach for tumors carrying mutated cohesin."

Journal • Synthetic lethality • Oncology • CTNNB1 • MYC • NIPBL • RAD21 • SMC1A • STAG2

Ambient particulate matter exposure induces ferroptosis in hippocampal cells through the GSK3B/Nrf2/GPX4 pathway. (PubMed, Free Radic Biol Med) - "Moreover, treatment with LY2090314 resulted in the upregulation of Nrf2 and GPX4, along with the facilitation of nuclear translocation of Nrf2. This study suggested that PM-induced ferroptosis in hippocampal cells may be via the GSK3B/Nrf2/GPX4 pathway."

Journal • CNS Disorders • GPX4

Interleukin-21 Drives a Hypermetabolic State and CD4 T Cell-associated Pathogenicity in Chronic Intestinal Inflammation. (PubMed, Gastroenterology) - "IL-21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL-21-induced metabolism in Tregs may mitigate CD4 T cell-driven chronic intestinal inflammation."

Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Metabolic Disorders • CD4 • IL1R1 • IL21 • VDAC1

Repurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies (ASH 2023) - "Strikingly, LY2090314 and CHIR99021 were effective at low nanomolar concentrations in B- and T-cell malignancies that expressed lymphoid Ikaros factors... B- and T-lymphoid malignancies not only lacked expression of β-catenin but critically depend on GSK3B for effective β-catenin degradation. Our interactome studies in lymphoid tumors revealed that β-catenin formed repressive complexes with lymphoid-specific Ikaros and NuRD complex factors. Strikingly, GSK3B small molecule inhibitors engage this new pathway at low nanomolar concentrations and demonstrated favorable safety profiles in Phase 1 and Phase 2 trials."

Alzheimer's Disease • CNS Disorders • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Melanoma • Movement Disorders • Oncology • Parkinson's Disease • Solid Tumor • T Acute Lymphoblastic Leukemia • T Cell Non-Hodgkin Lymphoma • CEBPA • CHD4 • HDAC1 • IKZF1 • IKZF3 • TCF7

Wnt/β-Catenin Signaling Activation Induces Differentiation in Human Limbal Epithelial Stem Cells Cultured Ex Vivo. (PubMed, Biomedicines) - "Therefore, we sought to explore the impact of canonical Wnt/β-catenin signaling activation on hLESCs by treating ex vivo expanded hLESC cultures with GSK-3 inhibitor LY2090314...No significant differences were found for WNT2, WNT16B, WIF1, and DKK2 gene expression. Overall, our results demonstrate that activation of Wnt/β-catenin signaling in ex vivo expanded hLESCs governs the cells towards differentiation and reduces proliferation and stem cell maintenance capability."

Journal • Preclinical • Transplantation • DKK1 • PCNA • SOX9 • TP63 • WIF1 • WNT11 • WNT3 • WNT7A

Elraglusib (formerly 9-ING-41) possesses potent anti-lymphoma properties which cannot be attributed to GSK3 inhibition. (PubMed, Cell Commun Signal) - "To confirm the importance of its action on GSK3β, we treated 3 lymphoma cell lines with selective, structurally distinct GSK3 inhibitors: CT99021, SB216763, LY2090314, tideglusib, and elraglusib. These data question GSK3 as the target of elraglusib in lymphoma, and hence the utility of GSK3 expression as a 'stand-alone', therapeutic biomarker in NHL. Video Abstract."

Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CTNNB1

Aberrant Glycogen Synthase Kinase 3 Activation In Liver Sinusoidal Endothelial Cells Enhances Liver Inflammation In Nonalcoholic Steatohepatitis (VASCULAR DISCOVERY 2023) - "PA also promoted the LSEC pro-inflammatory response by upregulating CXCL2 and intracellular adhesion molecule 1 (ICAM-1), all of which were attenuated with the GSK3 inhibitor LY2090314 (LY)...Furthermore, we confirmed increased LSEC expression of ICAM1 in human with NASH. In conclusion, GSK3 inhibition attenuates toxic lipid induced LSEC pro-inflammatory phenotype and may serve as a potential therapeutic strategy in human NASH."

Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis • ICAM1

Identifying modulators of YAP/TAZ activity in Glioblastoma Stem Cells (EACR 2023) - "There are few therapeutic options other than the current standard of care, which consists of surgery followed by concomitant radiotherapy and temozolomide...Analysis was performed using a combination of CellProfiler, StratoMiner and RStudio.Results and DiscussionsScreening identified 32 compounds of interest, 12 of which continued to show activity against YAP/TAZ in secondary dose response analysis; these included Dasatinib, eCF506, LY2090314 and Ouabain...Ouabain and LY2090314 could selectively modulate TAZ, but not YAP, localisation and induce apoptosis. This demonstrates high-content screening as a effective tool discover selective upstream modulators of YAP and TAZ cellular localisation in GSCs."

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

Development of a platform of 3D adipogenesis to model, at higher scale, the impact of LY2090314 compound on fibro/adipogenic progenitor adipogenic drift. (PubMed, Dis Model Mech) - "To predict the beneficial impact of LY2090314 in limiting ectopic deposition of fat in human muscles, we combined the Poly-Ethylene-Glycol-Fibrinogen biomimetic matrix with these progenitor cells to create a miniaturized 3D model of adipogenesis. Using this scalable system, we demonstrated that a two-digit nanomolar dose of this compound is effective to repress adipogenesis in a higher 3D scale, thus offering a concrete proof for the use of LY2090314 to limit FAP-derived fat infiltrates in dystrophic muscles."

Journal • Muscular Dystrophy

Small molecule drugs promote repopulation of transplanted hepatocytes by stimulating cell dedifferentiation. (PubMed, JHEP Rep) - "Netarsudil (N) and LY2090314 (L), two clinically used drugs which target the same pathways as YC, could also promote hepatocyte proliferation in vitro and in vivo, by facilitating HPC conversion. However, one important obstacle to hepatocyte therapy is the low level of engraftment and proliferation of the transplanted hepatocytes. Herein, we show that small molecule compounds which promote hepatocyte proliferation in vitro by facilitating dedifferentiation, could promote the growth of transplanted hepatocytes in vivo and may facilitate the application of hepatocyte therapy."

Journal • Hepatology • Transplantation

GSK3β Inhibition Is a Unique Vulnerability in Lymphoid Malignancies (ASH 2022) - "Four of the six GSK3β inhibitors (LY2090314, 6-Bromoindirubin-3'-oxime, CHIR98014 and CHIR99021) induced cell death at nanomolar concentrations selectively in lymphoid but not myeloid or epithelial cells...These results based on 18 clinical trials suggest that prolonged treatment at high (micromolar) concentrations is safe, however, lacks efficacy in solid tumors. Here we propose to repurpose GSK3β-inhibitors for the treatment of B- and T-lymphoid malignancies based on targeted engagement of repressive β-catenin:IKZF1 complexes."

Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • IKZF1 • MYC • TCF7

Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin-Induces Cell Cycle Arrest in a Glycogen Synthase Kinase (GSK)-3-Dependent Manner in Oral Keratinocytes. (PubMed, Int J Mol Sci) - "All three exhibited G2/M arrest when exposed to AaCdt toxin within 24 h. Toxin-treated cells exhibited reduced levels of pAkt and pGSK3β within 6 h. Pre-treatment with GSK3β kinase inhibitors, LY2090314, CHIR99021 and Tideglusib, abrogated Cdt-induced G2/M arrest. Cdt-treated cells displayed increased phosphorylation of the cyclin dependent kinase 1 (CDK1); moreover, the GSK3 inhibitors blocked this increase and reduced total CDK1 levels. This study further clarifies the potential mechanism(s) contributing to Cdt toxicity and toxin-mediated pathogenesis."

Journal • Dental Disorders • Periodontitis • CDK1

Molecular docking study of GSK-3β interaction with nomilin, kihadanin B, and related limonoids and triterpenes with a furyl-δ-lactone core. (PubMed, J Biochem Mol Toxicol) - "Numerous inhibitors of GSK-3β have been discovered but thus far only a few have reached clinical trials and only one drug, tideglusib (1), has been registered...The formation of GSK-3β-binding complexes for those natural products was compared to reference GSK-3β ATP-competitive inhibitors LY2090314 (3) and AR-A014418 (2)...Compound structure-binding relationships are discussed. The study should help the discovery of novel natural products targeting GSK-3β."

Journal • CNS Disorders • Infectious Disease • Oncology • GSK3B

GLYCOGEN SYNTHASE KINASE 3 INHIBITION REDUCES LIVER INFLAMMATION IN MURINE NONALCOHOLIC STEATOHEPATITS (DDW 2022) - "Using the same mouse NASH model, the GSK3 inhibitor LY2090314 (LY) or vehicle were intraperitoneally administered 3 times a week for the last 4 weeks of the study...Conclusion : GSK3 inhibition attenuates liver injury and inflammation in murine NASH and reduces the lipotoxic stress-induced proinflammatory phenotype of LSECs. These data suggest that GSK3 inhibition is a potential therapeutic strategy in human NASH."

Preclinical • Hepatology • Immunology • Inflammation • Liver Failure • Non-alcoholic Steatohepatitis • CCL2 • CXCL3

Novel patient-derived xenograft and cell line models for therapeutic screening in NF2-associated schwannoma. (PubMed, J Pathol) - "Using high-throughput screening of 157 inhibitors targeting the PI3K/AKT/mTOR pathways in vitro, we identified a dozen inhibitors (such as BEZ235, LY2090314, and AZD8055) with significant growth-suppressive effects...Furthermore, we demonstrated two orally bioavailable inhibitors AZD8055 and PQR309 suppressed NF2-associated schwannoma growth both in vitro and in vivo...Furthermore, we demonstrated two orally bioavailable inhibitors AZD8055 and PQR309 suppressed NF2-associated schwannoma growth both in vitro and in vivo. In conclusion, our novel patient-derived models of NF2-associated schwannoma closely mimic the phenotypes and genotypes of patient tumors, making them reliable preclinical tools for testing novel personalized therapies."

Journal • Preclinical • Brain Cancer • Fibrosis • Genetic Disorders • Neurofibromatosis • Oncology • Rare Diseases • Solid Tumor • NF2

Proposed hypothesis of GSK-3 β inhibition for stimulating Wnt/β-catenin signaling pathway which triggers liver regeneration process. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Various signaling pathways for liver regeneration are HO-1/BER pathway, Tweak/Fn14 signaling pathway, Hippo pathway, Wnt/beta-catenin pathway, Hedgehog signaling pathway, bile acids repairing pathway, serotonin (5HT) pathway, estrogen pathway, thyrotropin-releasing hormone (TRH) pathway, insulin repairing pathway, etc. The in vitro scientific literature revealed that numerous GSK-3 β inhibitors (LY 2090314, AR-A014418, Tideglusib, Solasodine, CHIR99021, 9-ING-41, SB-216763) play an important role in stimulating the liver regeneration process. Similarly, from the above discussion, the direction is highlighted to emphasize the proposed molecular Wnt/β-catenin signaling pathway which is associated with GSK-3 β inhibition for the induction of the repairing and regeneration process."

Journal • Hepatology • Transplantation

Beta-Catenin Forms Repressive Complexes with Ikzf1 and Ikzf3 to Orchestrate Tumor-Suppression in B-Cell Malignancies (ASH 2021) - "Strikingly, pan-cancer analysis of activating mutations of β-catenin in patient samples and global proteomic analysis of human cancer cell lines revealed that B-cell malignancies are exempt from oncogenic activation of β-catenin. While nuclear accumulation of β-catenin was observed in >80% of cancer samples studied, nuclear β-catenin was consistently absent in normal and malignant B-lymphoid cells. To model the effects of inducible β-catenin activation in B-ALL, pre-B cells from Ctnnb1 ex3fl /+ mice were transformed with BCR-ABL1 or NRAS G12D oncogenes."

Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Thoracic Cancer • ABL1 • BCR • CEBPA • CHD4 • CTNNB1 • HDAC1 • IKZF1 • IKZF3 • MYC • NRAS