LY2090314 / Eli Lilly - LARVOL DELTA

Targeting β-catenin nuclear export and protein degradation in high-risk acute lymphoblastic leukemia (ASH 2025) - "The combination of Selinexorwith GSK3B inhibition (LY2090314) or PSMB8/PSMB9 inhibition (Zetomipzomib/ONX0914) resulted insynergistic nuclear β-catenin accumulation in reporter cells...The identification of β-catenin as an XPO1 cargo protein and thenucleus as a shelter from protein degradation provide a mechanistic rationale for combining XPO1inhibition (selinexor, eltanexor) with GSK3B or immunoproteasome inhibition, which will support thedesign of forthcoming in vivo studies, including xenograft-based preclinical efficacy models in patient-derived B- and T-ALL xenografts. These findings identify β-catenin as a previously unrecognized and functionally significantcargo protein of XPO1 in B- and T-ALL... These findings identify β-catenin as a previously unrecognized and functionally significantcargo protein of XPO1 in B- and T-ALL. Our finding supports a promising combinatorial strategy for thetreatment of r/r ALL by co-targeting nuclear export and β-catenin protein..."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • PSMB8 • PSMB9 • XPO1

Identification of NAE1-dependent β-catenin neddylation as selective vulnerability in B-cell malignancies (ASH 2025) - "Importantly, both pevonedistat and TAS4464 strongly synergized with the GSK3B inhibitorLY2090314 in patient-derived B-ALL, mantle cell lymphoma and CLL samples.Conclusion. Based on CRISPR-screens, we discovered a novel B-cell-selective high-efficiency complex forβ-catenin protein degradation, which depends on NAE1-dependent neddylation. Given the surprising B-cell-selectivity of this mechanism, our findings support a rationale to repurpose clinically tested NAE1-inhibitors for the treatment of refractory B-cell malignancies as single agent or in combination withGSK3B inhibitors."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • Targeted Protein Degradation • ABL1 • AXIN1 • BCR • CTNNB1 • FBXO11 • MYC • PTPRC • UBA3

Harnessing repressive LEF1/β-catenin complexes to overcome drug resistance in chronic lymphocytic leukemia (ASH 2025) - "In aconverse experiment, tamoxifen induced stabilization of β-catenin (Mb1-Cre-ERT2 x Ctnnb1ex3/+)subverted leukemogenesis: while 7 out of 11 wildtype littermates developed CLL (median survival=426days), none of 11 mice with B-cell-specific β-catenin stabilization succumbed to CLL (P=0.02).Interestingly, β-catenin stabilization in B-cells resulted in selective depletion of CD5+ CD19+ CLL cells,which express high levels of nuclear LEF1 (intracellular FACS) and spared CD5- CD19+ normal B-cells thatlack LEF1 expression. Three GSK3B inhibitors LY2090314, AZD1080 and CHIR99021 achieved favorable safety and PK/PDprofiles in previous clinical trials for solid tumors and neurological disorders. Our results provide arationale for repurposing GSK3B-inhibitors for the treatment of refractory and RT CLL."

Chronic Lymphocytic Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Richter's Syndrome • Solid Tumor • CD5 • CTNNB1 • IKZF1 • LEF1 • MYC

Identification of immunomodulatory compounds by high-throughput proteomics: insights from quantification of 1000 proteins in a 20,000 sample screen (SITC 2025) - "We identified 68 cytotoxic compounds; of note, while most of these reduced cytokine expression, doxorubicin induced cytokine expression even at non-toxic doses, consistent with its reported pro-inflammatory properties. Other notable exceptions included the GSK-3 inhibitor LY2090314, and the BET inhibitor (+)-JQ1, which were toxic at higher doses, but induced the expression of distinct chemokines at lower doses...For example, the Met inhibitor PF-04217903 potently induced CXCL9-10 and IL-12 expression by hepatocytes, with no signs of toxicity. Considering that PF-04217903 was well tolerated in the clinic but was not pursued for strategic reasons, our results suggest potential for development in combination with checkpoint inhibitors for Met-driven tumors.Conclusions Our results demonstrate the value of high-throughput proteomics to identify new immunomodulatory compounds and simultaneously characterize their safety profile."

Immunomodulating • IO biomarker • Oncology • CASP3 • CXCL9 • EIF2A • EIF2S1 • GAPDH • IL12A • IL6 • MAPK3 • TNFA

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

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

Structural and functional characterization of TgGSK3, a druggable kinase in Toxoplasma gondii. (PubMed, Nat Commun) - "Moreover, therapeutic alternatives remain limited or nonexistent, particularly for cryptosporidiosis, for which nitazoxanide is currently the only approved medication to treat diarrhea in adults and children older than 1 year of age...This screening identifies LY2090314 as a potent inhibitor of T. gondii and Cryptosporidium growth in mammalian cells...Furthermore, interactome analysis uncovers functional connections between TgGSK3 and key cytoskeletal and signaling regulators, providing insights into compound's effects. Collectively, these findings validate TgGSK3 as a promising therapeutic target for toxoplasmosis and offer mechanistic insights into apicomplexan GSK3 biology."

Journal • Infectious Disease

Pretreatment with LY2090314, a potent glycogen synthase kinase-3 inhibitor, suppresses methamphetamine-induced stereotyped behavior but not hyperlocomotion in mice. (PubMed, Behav Pharmacol) - "GSK-3 signaling pathways appear to be differentially involved in acute METH effects on locomotion. GSK-3 appears essential for the expression of METH-induced stereotypy but not hyperlocomotion."

Journal • Preclinical

A Combination Therapy Strategy That Targets Both KRAS-G12C and GSK3 for Non-Small Cell Lung Cancer (IASLC-WCLC 2025) - "KRAS mutants, including G12C, are critical cancer drivers that used to be difficult to drug Despite progresses in allosteric KRAS-G12C inhibitors, e.g. sotorasib and adagrasib,, their drug response is still suboptimal...Results : The GSK3 inhibitor LY2090314 emerges as a compound that sensitizes NSCLC cell lines to KRAS G12C inhibitors...Figure. High-throughput drug screening reveals that GSK3 inhibition synergistically enhances the efficacy of KRAS G12C inhibitors in KRAS G12C-mutant lung cancer."

Combination therapy • Hematological Malignancies • Leukemia • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • KRAS

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

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

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