LY-411575 / Eli Lilly - LARVOL DELTA

Segetalin B Promotes Bone Formation in Ovariectomized Mice by Activating PLD1/SIRT1 Signaling to Inhibit γ-Secretase-Mediated Notch1 Overactivation. (PubMed, J Steroid Biochem Mol Biol) - "The effects of SB, PLD1 inhibitor VU0359595, SIRT1 inhibitor EX527, and γ-secretase inhibitor LY-411575 were examined. This cascade promotes bone formation by upregulating Wnt/β-catenin signaling. Combining SB with LY-411575 may offer a novel therapeutic strategy for postmenopausal osteoporosis."

Journal • Preclinical • Osteoporosis • Rheumatology • NOTCH1

Luteolin ameliorates ulcerative colitis in mice via reducing the depletion of NCR+ILC3 through Notch signaling pathway. (PubMed, Chin J Nat Med) - "In addition, luteolin increased the proportion of NCR+ILC3, NCR+MNK3 and IL-22+ILC3, decreased intestinal permeability, promoted mucin secretion, and promoted ZO-1 and Occludin expression, the above effect of luteolin was neutralized by Notch inhibitor LY-411575...And molecular docking predicted the affinity of luteolin for RBPJ to be -7.5 kcal·mol-1 in mouse, respectively; the affinity of luteolin for Notch1 and RBPJ was respectively scored to be -6.4 kcal·mol-1 and -7.7 kcal·mol-1 homo sapiens. These results proved that luteolin is positive for enhancing the proportion of NCR+ILC3 via Notch signaling, and it provides a basis for targeting NCR+ILC3 for restoring intestinal barrier function to alleviating ulcerative colitis."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • IL22 • NOTCH1 • OCLN • TJP1

Effect of sex hormones on the kinetics of amyloid-beta in an awake and behaving mouse (Neuroscience 2024) - "Animals were then dosed with LY 411575, a gamma secretase inhibitor that blocks the production of Aβ, in addition to beta-estradiol...Animals injected intraperitoneally with progesterone show similar results, suggesting that peripheral progesterone signaling is sufficient to cause the decrease seen in Aβ. These novel results suggest a differential effect of the two most prevalent sex steroids in females, and work is ongoing to uncover the cause of this effect."

Preclinical • Alzheimer's Disease • CNS Disorders • MMP9

TL1A and IL-18 synergy promotes GM-CSF-dependent thymic granulopoiesis in mice. (PubMed, Cell Mol Immunol) - "NOTCH blockade by the LY411575 inhibitor increased the number of neutrophils in the culture, indicating that NOTCH restricted steady-state thymic granulopoiesis...In support, TL1A- and IL-18-induced granulopoiesis was completely prevented in NTOCs derived from Csf2rb-/- mice and by GM-CSFR antibody blockade, revealing that GM-CSF is the essential factor driving thymic granulopoiesis. Taken together, our findings reveal that TL1A and IL-18 synergism induce acute thymus atrophy while  promoting extramedullary thymic granulopoiesis in a NOTCH and GM-CSF-controlled manner."

Journal • Preclinical • Cytomegalovirus Infection • Infectious Disease • Inflammation • Pneumonia • Respiratory Diseases • CSF2 • IL18 • RAG1

An Essential Role of c-Fos in Notch1-mediated Promotion of Proliferation of KSHV-Infected SH-SY5Y Cells. (PubMed, Curr Mol Pharmacol) - "Our findings strongly indicate that c-Fos plays a crucial role in the promotion of cell proliferation through Notch1 signaling in KSHV-infected cells. Furthermore, our results suggest that the inhibition of expression of key viral pathogenic proteins is likely involved in this process."

Journal • Kaposi Sarcoma • Oncology • Sarcoma • Solid Tumor • CCND1 • CDK4 • CDK6 • FOS • NOTCH1

Identification of signalling pathways involved in gill regeneration in zebrafish. (PubMed, J Exp Biol) - "We screened for the effects on regeneration of the drugs, SU5402, dorsomorphin, and LY411575 that inhibit FGF, BMP or Notch signalling pathways, respectively. In situ hybridization confirmed that all four genes were expressed in regenerating gill tissue. This study implicates BMP, FGF, Notch and Shh signalling in gill regeneration in zebrafish."

Journal • BMP2

γ-Secretase Inhibitor Potentiates the Activity of Suberoylanilide Hydroxamic Acid by Inhibiting Its Ability to Induce Epithelial to Mesenchymal Transition and Stemness via Notch Pathway Activation in Triple-Negative Breast Cancer Cells. (PubMed, ACS Pharmacol Transl Sci) - "Therefore, we have focused on combination therapy using a γ-secretase inhibitor LY411575 that would enhance the efficacy of SAHA by blocking the canonical Notch pathway mediated via its intracellular domain. Besides, it also mediates autophagy-independent cell death and diminishes the expression of inflammatory cytokines, along with the downregulation in the expression of the Notch downstream genes and mesenchymal markers. Altogether, our study provides a mechanistic basis for combating EMT potentiated by SAHA, which could be utilized as a rational strategy for the treatment of solid tumors, especially triple-negative breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HES1 • MYC

CD151 Expression Reflects Different Features in Cardiac Subtype Specification From Human Pluripotent Stem Cells (AHA 2022) - "To reveal that Notch signaling inhibits atrial specification, we analyzed ACMs treated with LY411575, a Notch signaling inhibitor... Our results demonstrate that the CD151 expression indicates mitotic activity in VCMs. CD151high VCMs are more advanced specified VCMs with binucleation without cell proliferation. On the other hand, in ACMs, CD151 works as an indicator of Notch signaling, which suppresses atrial specification."

Heart Failure

Cisplatin attenuates taste cell homeostasis and induces inflammatory activation in the circumvallate papilla. (PubMed, Theranostics) - "LY411575 treatment could offset the increased number of Pax1 or Pycr1 cells induced by cisplatin in the circumvallate papilla and taste organoids. This study highlights the inhibitory effects of cisplatin on taste cell homeostasis and function, identifies critical genes and biological processes regulated by chemotherapy, and proposes potential therapeutic targets and strategy for taste dysfunction in cancer patients."

Journal • Inflammation • Oncology

NOTCH pathway inactivation reprograms stem-like oral cancer cells to JAK-STAT dependent state and provides the opportunity of synthetic lethality. (PubMed, Transl Oncol) - "Study revealed for the first time that NOTCH pathway-inactive state exhibit activation of JAK-STAT pathways, as synthetic lethal pair. Therefore, co-inhibition of these pathway may serve as novel therapeutic strategy against aggressive oral cancer."

Journal • Synthetic lethality • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • STAT3

Inhibition of Notch reverses immunosuppression in basal-like breast cancer (AACR 2023) - "Using a crossover design, mice were randomly allocated to treatment with either Notch inhibitor (γ-secretase inhibitor, LY411575), anti-PD1 (RMP1-14), or control treatment for 12-days (stage-1), followed by randomization to a second 12-day period (stage 2) with the same, or one of the other treatments... Despite the low response rate of BLBC to ICB alone, Notch inhibition reduced TAMs and induced responsiveness to sequential ICB. This response was characterized by increased cytotoxic T lymphocytes (GrB+, CTL) infiltration of the primary tumor. Similar results were observed when Notch-regulated cytokines (IL-1β and CCL2), crucial to TAM recruitment, were inhibited."

Breast Cancer • Lung Cancer • Melanoma • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • CCL2 • IL1B

Gamma secretase activity modulates BMP-7-induced dendritic growth in primary rat sympathetic neurons. (PubMed, Auton Neurosci) - "BMP-7-induced dendritic growth was inhibited by siRNA knockdown of PSEN1 and by three γ-secretase inhibitors, γ-secretase inhibitor IX (DAPT), LY-411575 and BMS-299897. In summary, our results indicate that γ-secretase activity enhances BMP-7 induced dendritic growth in sympathetic neurons. These findings provide insight into the normal cellular role of the γ-secretase complex in sympathetic neurons."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • APH1A

Tibetan medicine Qi-Sai-Er-Sang-Dang-Song Decoction inhibits TNF-α-induced rheumatoid arthritis in human fibroblast-like synoviocytes via regulating NOTCH1/NF-κB/NLRP3 pathway. (PubMed, J Ethnopharmacol) - "This study reveals that the QSD can markedly ameliorate inflammation induced by TNF-α on HFLS. The effect of QSD on HFLS may be exerted by inhibition of the NOTCH1/NF-κB/NLRP3 signaling pathway."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Pain • Rheumatoid Arthritis • Rheumatology • HES1 • IL18 • IL1B • IL6 • NF-κβ • NLRP3 • NOTCH1 • TNFA

Γ-Secretase Inhibitors Enhance the Potency of BCMA-Targeting T Cell Engagers Against Multiple Myeloma Cells without Adverse Impact on T-Cell Activation and Differentiation (ASH 2022) - "LY411575 is most effective, showing ~2-log greater potency than DAPT in all tested MM cell lines and patient MM cells regardless of baseline BCMA expression and statuses of disease and drug resistance...Moreover, a single treatment with GSI at ~ 2-log lower drug concentration than used to induce anti-cancer activity maximizes mBCMA density without harming normal cells. Rationally incorporating GSI into all BCMA-targeting immunotherapy therefore represents a promising novel combination approach to further improve patient outcome in MM."

IO biomarker • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • CD8 • HAVCR2 • IFNG • IL10 • IL2 • LAG3 • LAMP1 • PD-1 • SDC1 • TGFB1 • TIGIT • TNFA

Supervised machine learning reveals the heterogeneous changes of gait kinematics in response to β amyloid level alteration in a mouse model of neurodegeneration (Neuroscience 2022) - "Next, we delivered GSI (Benzodiazepine-type LY-411575, oral gavage daily for four consecutive days) to all the animals and collected kinematic features of quadrupedal treadmill stepping after 4 days of GSI treatment...We used a random-forest classification model trained on a no GSI treatment, kinematics dataset, but failed to predict the genotype of the animals with GSI treatment for both WT and J20 mice. This inconsistency between the computational prediction based on kinematics features and the motor behavioural results suggests that GSI may negatively impact quadrupedal kinematics features unrelated to the maximum stepping speed and the steps with drag."

Heterogeneity • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • APP

Notch signaling-induced cyclin d1 in diabetes ameliorating effects of the isolated polysaccharide from Rosa canina: In vitro and in vivo studies. (PubMed, Cell Biochem Funct) - "Notch inhibition by LY-411575 was associated with the downregulation of cyclin d1 which upregulates with polysaccharide treatment. The significant expression of cyclin d1 (90%) and nuclear expression of hes1 in the pancreas of the polysaccharide group were accompanied by improvement of hyperglycemia and associated biochemical factors as well as regeneration of islet cells as compared to untreated diabetic rats. Based on these findings, upregulation of Notch signaling-induced cyclin d1 could be proposed as the underlying diabetes-reducing effects of the isolated polysaccharide derivative implying that cyclin d1 actuation through activation of the Notch-DLL4 circuit may play the causal role in the treatment of diabetes."

Journal • Preclinical • Diabetes • Metabolic Disorders • CCND1 • HES1 • NOTCH1 • PDX1

Anti-angiogenic effects of aqueous extract from Agrostemma githago L. seed in human umbilical vein endothelial cells via regulating Notch/VEGF, MMP2/9, ANG2, and VEGFR2. (PubMed, Environ Sci Pollut Res Int) - "Furthermore, a γ-secretase inhibitor (LY411575) was applied to determine whether Notch inhibition restores A. githago effects...Inhibition of Notch signaling retrieved the viability loss, reduced intracellular ROS, and alleviated the impaired tube formation in A. githago-treated HUVECs. Overall, these data underscore the anti-angiogenic potential of A. githago via inducing apoptosis, modifying the expression levels of VEGF/VEGFR2, and impacting the release of MMP2/9 and ANG2, effects that are most probably modulated through the Notch/VEGF signaling axis."

Journal • KDR • MMP2 • MMP9 • NOTCH1

γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation. (PubMed, Blood Cancer J) - "GSIs, i.e., 2 nM LY-411575 or 1 μM DAPT, robustly increased mBCMA densities on CD138 but not CD3 patient cells, concomitantly with minimum soluble/shed BCMA (sBCMA) in 1 day-culture supernatants...Importantly, LY41157 rapidly cleared sBCMA from circulation of MM-bearing NSG mice reconstituted with human T cells and significantly enhanced anti-MM efficacy of PL33 with prolonged host survival. Taken together, these results further support ongoing combination BCMA-targeting immunotherapies with GSI clinical studies to improve patient outcome."

IO biomarker • Journal • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • CD4 • CD8 • HAVCR2 • IFNG • IL2 • LAG3 • LAMP1 • PD-1 • SDC1 • TIGIT • TNFA

γ-secretase inhibitors augment efficacy of BCMA-targeting T cell engagers against multiple myeloma cells without impairing T cell effector function (IMW 2022) - "LY411575 is most effective, showing ~2-log greater potency than DAPT in all tested MM cell lines and patient MM cells... GSI inhibits mBCMA loss from MM cells and overcomes the sBCMA decoy neutralization, leading to further improved efficacy of BCMAxCD3 BisAbs without adverse impacts on activation and differentiation of patient T cells. Rationally incorporating GSI into all BCMA-targeting immunotherapy therefore represents a promising novel combination approach to improve patient outcome in MM."

Clinical • IO biomarker • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • CD8 • HAVCR2 • IFNG • IL10 • IL2 • LAG3 • LAMP1 • PD-1 • SDC1 • TGFB1 • TIGIT • TNFA

Identification of MAEL as a promoter for the drug resistance model of iPSCs derived from T-ALL. (PubMed, Cancer Med) - "Furthermore, overexpression of the MAEL gene enhanced drug resistance against LY411575. Conclusively, MAEL promotes LY411575 resistance in T-ALL cells increasing the expression of MRP and LRP genes."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • KLF4 • NOTCH1 • POU5F1 • SOX2

Amyloid beta deposition in the lumbosacral spinal circuit impairs both the short-term and long-term neuroplasticity of locomotion (Neuroscience 2021) - "The spontaneous bipedal locomotion recovery was also inhibited in spinal J20 mice when compared to WT littermates (p = 0.0031). Notably, these impairments of lumbar circuit plasticity was reversed by the administration of a gamma-secretase inhibitor (Benzodiazepine-type LY-411575) in the spinal J20 mice, suggesting the generation of amyloid-beta in local spinal cord circuit contribute to the locomotor deficits.; Grant Support: J. Yang Family Foundation; H & H Evergreen Foundation; Louis and Harold Price Foundation"

Alzheimer's Disease • CNS Disorders • APP

DR-5 and DLL-4 mAb Functionalized SLNs of Gamma-Secretase Inhibitors- An Approach for TNBC Treatment. (PubMed, Adv Pharm Bull) - "Further, the GSIs (DAPT, LY-411575, RO4929097, MK0752, etc.) suffer from poor bioavailability and off-target side effects such as diarrhea, suppression of lymphopoiesis, headache, hypertension, fatigue, and ventricular dysfunctions. The delivery system is designed to deliver the drug cargo precisely to TNBCs through its DR-5 receptors and hence expected to reduce the off-target side effects of GSIs. Further, DLL4 mAb and GSIs are expected to act synergistically to block the Notch signal mediated BCSCs proliferation, differentiation, and metastasis."

Journal • Review • Breast Cancer • Cardiovascular • Fatigue • Heart Failure • Hypertension • Oncology • Pain • Solid Tumor • Triple Negative Breast Cancer • TNFRSF10B

Soluble β-amyloid impaired the GABA inhibition by mediating KCC2 in early APP/PS1 mice. (PubMed, Biosci Trends) - "When we treated 3-4 months APP/PS1 mice with a potent γ-secretase inhibitor, LY411575, which can reduce the soluble Aβ42 levels, the TNF-α and BDNF protein levels were decreased, while KCC2 and GABAR levels were increased. In conclusion, our study suggested soluble Aβ may impaired the GABA inhibition by mediating KCC2 levels in early APP/PS1 mice. KCC2 may be served as a potential biomarker for AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • BDNF • TNFA

Notch-1 and Notch-3 Mediates Hypoxia-Induced Synovial Fibroblasts Activation in Rheumatoid Arthritis. (PubMed, Arthritis Rheumatol) - "Collectively, this study has identified a functional link between HIF-1α, Notch-1, and Notch-3 signalling in regulating RASFC activation and rheumatoid arthritis."

Journal • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • HIF1A • NOTCH1 • NOTCH3

Treatment of collagen-induced arthritis rat model by using Notch signalling inhibitor. (PubMed, J Orthop Translat) - "Methotrexate and sodium carboxymethyl cellulose (CMC-Na) were used as positive and negative (vehicle) control respectively. The inhibitor of Notch signalling LY411575 is an effective treatment for CIA. Our study provides new evidence to support the potential clinical application of Notch signalling pathway inhibitor LY411575 as a drug candidate for the treatment of RA."

Journal • Preclinical • Immunology • Inflammation • Inflammatory Arthritis • Osteoporosis • Rheumatoid Arthritis • Rheumatology • NOTCH1 • NOTCH3