Structure of LY294002
CAS No.: 154447-36-6
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
LY294002 is a PI3K inhibitor with IC50 values of 0.5 μM for PI3Kα, 0.57 μM for PI3Kδ, and 0.97 μM for PI3Kβ. LY294002 has anti-tumor effects and is used to study the PI3K/AKT signaling pathway and related cancer treatments.
Synonyms: SF 1101; NSC 697286
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Keratin 19 interacts with GSK3β to regulate its nuclear accumulation and degradation of cyclin D3
Sharma, Pooja ; Tiufekchiev, Sarah ; Lising, Victoria ; Chung, Seung Woo ; Suk, Jung Soo ; Chung, Byung Min
Abstract: Cyclin D3 regulates the G1/S transition and is frequently overexpressed in several cancer types including breast cancer, where it promotes tumor progression. Here we show that a cytoskeletal protein keratin 19 (K19) phys. interacts with a serine/threonine kinase GSK3β and prevents GSK3β -dependent degradation of cyclin D3. The absence of K19 allowed active GSK3β to accumulate in the nucleus and degrade cyclin D3. Specifically, the head (H) domain of K19 was required to sustain inhibitory phosphorylation of GSK3βSer9, prevent nuclear accumulation of GSK3β,and maintain cyclin D3 levels and cell proliferation. K19 was found to interact with GSK3β and K19-GSK3β interaction was mapped out to require Ser10 and Ser35 residues on the H domain of K19. Unlike wildtype K19, S10A and S35A mutants failed to maintain total and nuclear cyclin D3 levels and induce cell proliferation. Finally, we show that the K19-GSK3β-cyclin D3 pathway affected sensitivity of cells toward inhibitors to cyclin-dependent kinase 4 and 6 (CDK4/6). Overall, these findings establish a role for K19 in the regulation of GSK3β-cyclin D3 pathway and demonstrate a potential strategy for overcoming resistance to CDK4/6 inhibitors.
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Wu, Likang ; Xu, Lei ; Chen, Yu ; Xu, Guohua ; Guo, Qunfeng ; Meng, Depeng , et al.
Abstract: Background: Fibrosis is an important factor and process of ligamentum flavum hypertrophy. The expression of phosphodiesterase family (PDE) is related to inflammation and fibrosis. This article studied the expression of PDE in hypertrophic ligamentum flavum fibroblasts and investigated whether inhibition of PDE4 activity can play an anti-fibrotic effect. Methods: Samples of clinical hypertrophic ligamentum flavum were collected and patients with lumbar disc herniations as a control group. The collagenase digestion method is used to separate fibroblasts. qPCR is used to detect the expression of PDE subtypes, type I collagen (Col I), type III collagen (Col III), fibronectin (FN1) and transforming growth factor β1 (TGF-β1). Recombinant TGF-β1 was used to stimulate fibroblasts to make a fibrotic cell model and treated with Rolipram. The morphology of the cells treated with drugs was observed by Sirius Red staining. Scratch the cells to observe their migration and proliferation. WB detects the expression of the above-mentioned multiple fibrotic proteins after drug treatment. Finally, combined with a variety of signaling pathway drugs, the signaling mechanism was studied. Results: Multiple PDE subtypes were expressed in ligamentum flavum fibroblasts. The expression of PDE4A and 4B was significantly up-regulated in the hypertrophic group. Using Rolipram to inhibit PDE4 activity, the expression of Col I and TGF-β1 in the hypertrophic group was inhibited. Col I recovered to the level of the control group. TGF-β1 was significantly inhibited, which was lower than the control group. Recombinant TGF-β1 stimulated fibroblasts to increase the expression of Col I/III, FN1 and TGF-β1, which was blocked by Rolipram. Rolipram restored the increased expression of p-ERK1/2 stimulated by TGF-β1. Conclusion: The expressions of PDE4A and 4B in the hypertrophic ligamentum flavum are increased, suggesting that it is related to the hypertrophy of the ligamentum flavum. Rolipram has a good anti-fibrosis effect after inhibiting the activity of PDE4. This is related to blocking the function of TGF-β1, specifically by restoring normal ERK1/2 signal.
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Keywords: Rolipram ; Phosphodiesterase ; Ligamentum Flavum hypertrophy ; ERK1/2 ; Fibrosis ; TGF-β1
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Regulation of Cell Cycle Progression by Keratin 19 in Breast Cancer Cells
Sharma, Pooja ;
Abstract: Keratins are widely used as diagnostic markers to detect tumors in both primary and distal sites and to determine tumors’ tissue of origin in order to aid in treatment strategies. In this regard, K19 has been particularly useful because it is among the most sensitive diagnostic markers across a broad range of cancer types. K19 has also been shown to be one of the most reliable prognostic markers for multiple tumor types, including breast cancer where higher expression of K19 is correlated with worse patient survival. Despite the clinical data showing positive correlation between increased K19 expression and poor survival rates among patients of breast cancer types, the role of K19 in breast cancer remains unclear. To understand the role of K19 in breast cancer, we generated KRT19 knockout (KO) cell lines using MCF7 and MDA-MB-231 breast cancer cell lines. Using this system, we found that KRT19 KO cells exhibit reduced proliferation compared to parental control cells and uncovered a cell cycle promoting role of K19. We identified that K19 promotes proliferation of cancer cells by stabilizing a cell cycle regulator cyclin D3. However, how a cytoskeletal protein regulates levels of cyclin D3 remained unknown. It has been known that GSK3β play a crucial role in degrading cyclin D3 for proteasomal degradation. In our study in MCF7 cells, we identified GSK3β as a keratin-interacting protein and found that K19 suppressed GSK3β activity by inhibiting its nuclear accumulation. GSK3β-binding by K19 required serine 10 and 35 residue as K19 S10A or S35A mutation failed to protect cyclin D3 from protein degradation. Our results reveal a novel regulatory role of K19 on GSK3β localization and activity as a mechanism of how a cytoskeletal protein stabilizes a cell cycle regulator and promotes proper cell proliferation. In addition, we found that K19 expressing cells are more sensitive to cyclin dependent kinase (CDK) 4/6 inhibitors as compare to KRT19 KO cells. The sensitivity of KRT19 KO cells to CDK4/6 inhibitor was increased when cotreated with a GSK3β inhibitor, demonstrating that the K19-GSK3β axis plays a critical role in drug resistance. Given that K19 expression levels are frequently elevated in various cancers, K19 can be used to predict the efficacy of CDK4/6 inhibitors and patients may be cotreated with a GSK3β inhibitor to avoid drug resistance.
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| CAS No. : | 154447-36-6 |
| Formula : | C19H17NO3 |
| M.W : | 307.34 |
| SMILES Code : | O=C1C=C(N2CCOCC2)OC3=C1C=CC=C3C4=CC=CC=C4 |
| Synonyms : |
SF 1101; NSC 697286
|
| MDL No. : | MFCD00270881 |
| InChI Key : | CZQHHVNHHHRRDU-UHFFFAOYSA-N |
| Pubchem ID : | 3973 |
| GHS Pictogram: |
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| Signal Word: | Warning |
| Hazard Statements: | H302-H315-H319-H332-H335 |
| Precautionary Statements: | P261-P280-P305+P351+P338 |
| Target |
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In Vitro:
| Concentration | Treated Time | Description | References |
| BMSCs | 20 µM | 0, 15, 30, 60, 120 min | LY294002 significantly inhibited the higher expression of osteogenic genes induced by Ginsenoside Rb1. | Int J Oral Sci. 2022 Feb 14;14(1):10. |
| Astrocytes | 10 µM | 1 hour | AMPK inhibition reduces collective cell migration and invasion efficiency. | Nat Commun. 2022 Aug 11;13(1):4528. |
| TNBC cell lines | 2 µM | 10 days | To investigate the effect of MAPK4 knockdown on cell growth and sensitivity to PI3K inhibitors | Nat Commun. 2022 Jan 11;13(1):245. |
| HWJ-MSCs | 40 µM | 2 hours | Estimate the effects of the AKT inhibitor on the proliferation of FP2-cultured hWJ-MSCs. | J Adv Res. 2024 Aug;62:119-141. |
| SKMEL28 melanoma cells | 20 µM | 2 hours | The study involved the inhibition of AKT signaling to determine the effects on oxidative DNA damage repair; results showed reduced expression of OGG. | Redox Biol. 2024 Jun;72:103135. |
| U-251 and Ca9-22 cells | 20 µM | 2 hours | To assess the impact of PI-3 kinase inhibition on cell behavior. | Adv Sci (Weinh). 2023 Mar;10(7):e2207368. |
| ADSCs | 50 µM | 24 hours | To investigate the role of PI3K signaling on rGO/PCL induced neurotrophic phenotype changes and myelin protein secretion. | Bioact Mater. 2022 Jun 13;20:319-338. |
| MLE-12 cells | 50 μg/mL | 24 hours | LY294002 was used as a positive control to inhibit up-regulated expression of fibrosis-related genes. | J Nanobiotechnology. 2024 Oct 26;22(1):662. |
| RAW 264.7 | 10 µM | 24 hours | To evaluate the effect of LY294002 on macrophage polarization. | J Nanobiotechnology. 2024 Jun 8;22(1):322. |
| HESCs | 10 µM | 24 hours | To investigate the role of LY294002 in influencing differentiation to endoderm. | Nat Commun. 2023 Jan 25;14(1):405. |
| Primary chondrocytes | 10 µM | 24 hours | LY294002 administration significantly reduced SNP-induced apoptosis activities and alleviated aberrant force-induced chondrocyte degeneration. | Int J Oral Sci. 2022 Jul 14;14(1):34. |
| NHA/HRasV12/TRIM24 cells | 0.01 to 100 µM | 24, 48, and 72 hours | Cell proliferation was evaluated and the half-maximal inhibitory concentration (IC50) values were determined from fitted concentration-response curves. | Adv Sci (Weinh). 2024 Aug;11(29):e2400023. |
| Chondrocytes | 20 µM | 3 days | The study aims to investigate the effects of blood on chondrocyte viability and apoptosis. | Signal Transduct Target Ther. 2024 May 8;9(1):109. |
| H9C2 cells | 25 µM | 30 min | To explore the mechanisms of NGR1's protective effect on H9C2 cells. | Redox Biol. 2022 Aug;54:102384. |
| HAEC and HSMEC | 50 nM | 30 min | To evaluate the effect of LY294002 on insulin uptake. | Nat Commun. 2023 Aug 17;14(1):4989. |
| Vascular Smooth Muscle Cells (VSMC) | 50 µM | 30 min | To inhibit the activation of Akt and study the effects on related signaling pathways. | Redox Biol. 2022 Jun;52:102296. |
| Human fetal RPE cells | 2 µM | 4 days | To investigate the effect of glucose concentration on inflammatory responses, where inflammatory markers were evaluated. | Nat Commun. 2022 Oct 13;13(1):6045. |
| CTLL-2 cells | 50 µM | 48 hours | The purpose was to analyze the effect of LY294002 on the CTLL-2 cells in the presence of IL-7. | Bioact Mater. 2023 Sep 26;32:12-27. |
| RF24 cells | 50 µM | 6 hours | The treatment resulted in reduced angiogenesis as inferred from subsequent experiments. | Nat Commun. 2023 Apr 26;14(1):2407. |
| HUVECs | 5 μg/mL | 6, 24, 48, and 72 hours | To observe the effects of the PI3K inhibitor as a negative control | Biomaterials. 2022 Sep;288:121729. |
| Human embryonic stem cells | 5 µM | 8 days | Induction of neuroectoderm differentiation. | Nucleic Acids Res. 2024 May 22;52(9):4935-4949. |
| Astrocytes | 40 µM | To inhibit PI3K signaling pathway and evaluate its effects on glycophagy. | Redox Biol. 2024 Aug;74:103234. | |
| RAW264.7 cells | 25 µM | 1 h | Inhibit PI3K signaling pathway and reduce M1 macrophage polarization | J Transl Med. 2024 Aug 2;22(1):717. |
| BMDMs | 25 µM | 1 h | Inhibit PI3K signaling pathway and reduce M1 macrophage polarization | J Transl Med. 2024 Aug 2;22(1):717. |
| neonatal rat cardiomyocytes (NRCMs) | 10 μM | 2 h | Inhibited PI3K α/AKT signaling, reversed FGF7-mediated promotion of Nrf2 nuclear translocation, and increased ROS levels and apoptotic cells | Redox Biol. 2022 Oct;56:102468. |
| human dental pulp stem cells | 10 µM | 7 days | LY294002 attenuated the responsiveness of 10−6 M insulin to IIS/PI3K/AKT/mTOR pathway axis, suppressing the promoting effect of insulin on cell proliferation, osteogenic differentiation and bone formation. | Stem Cell Res Ther. 2024 Jul 29;15(1):227. |
| PC-9R cells | 25 μM | Inhibited the PI3K/AKT pathway and restored sensitivity to gefitinib in PC-9R cells | J Cancer. 2022 Mar 21;13(6):1837-1847. | |
| BMDMs | 0.5 μM | 2 h | Inhibited PI3K/Akt/Nrf2 signaling pathway and increased NLRP3/Caspase-1/GSDMD protein expression | Phytomedicine. 2023 Jun;114:154753. |
| A549 cells | 10μM | 1 h | Inhibited PI3K/AKT signaling pathway, alleviated TGF-β1-induced epithelial-mesenchymal transition (EMT) | Front Pharmacol. 2022 Mar 9;13:829673. |
| Huh7-SR cells | 5 µM | 1 h | Inhibited PI3K/Akt pathway, reduced Nrf2 nuclear translocation, and increased ferroptosis level | Front Oncol. 2022 Mar 22;12:852095. |
| HepG2-SR cells | 5 µM | 1 h | Inhibited PI3K/Akt pathway, reduced Nrf2 nuclear translocation, and increased ferroptosis level | Front Oncol. 2022 Mar 22;12:852095. |
| Mouse primary hepatocytes | 10 μM | 1.5 h | To evaluate the relationship between PI3K/AKT pathway and ferroptosis, LY294002 pretreatment exacerbated ferroptosis | Transplantation. 2024 Nov 1;108(11):e357-e369. |
In Vivo:
| Administration | Dosage | Frequency | Description | References |
| Mice | Experimental autoimmune hepatitis model | Intraperitoneal injection | 30 mg/kg | Pretreatment 30 minutes before | Inhibit PI3K signaling pathway and reduce FGF4's regulatory effect on M1 macrophages | J Transl Med. 2024 Aug 2;22(1):717. |
| C57BL/6 mice | Myocardial infarction model (LAD ligation) | Intraperitoneal injection | 2.5 mg/kg | From LAD operation to 7 days post-operation | Inhibited PI3K α/AKT signaling, abolished FGF7-mediated regulation of Nrf2 and HXK2, and exacerbated myocardial oxidative stress and apoptosis | Redox Biol. 2022 Oct;56:102468. |
| BALB/c nude mice | PC-9R cell xenograft model | Intraperitoneal injection | 2.5 mg/kg | Every three days for 12 days | LY294002 significantly reduced tumor volume and enhanced the anti-tumor effect of gefitinib | J Cancer. 2022 Mar 21;13(6):1837-1847. |
| C57BL/6 mice | Acute lung injury model | Injection | 20 mg/kg | 24 hours | Inhibited PI3K/Akt/Nrf2 signaling pathway and increased NLRP3/Caspase-1/GSDMD protein expression | Phytomedicine. 2023 Jun;114:154753. |
| Mice | Bleomycin-induced pulmonary fibrosis model | Intraperitoneal injection | 25 mg/kg | Every other day for 21 days | Inhibited PI3K/AKT signaling pathway, alleviated bleomycin-induced pulmonary fibrosis and EMT | Front Pharmacol. 2022 Mar 9;13:829673. |
| NOD mice | Diabetes model | Intraperitoneal injection | 75 mg/kg | Daily for 3 days | Inhibition of PI3K signaling pathway to observe its effect on CD4+ T cell migration | J Immunol. 2016 Nov 1;197(9):3504-3511 |
| NOD-SCID mice | Subcutaneous tumor model | Intraperitoneal injection | 25 mg/kg | Twice a week for 4 weeks | Inhibited PI3K/Akt pathway, slowed growth of FNDC5-overexpressing HCC cells, and increased ferroptosis level | Front Oncol. 2022 Mar 22;12:852095. |
| C57 mice | Liver warm ischemia/reperfusion model | Intraperitoneal injection | 10 mg/kg | Single dose 36 h before liver ischemia followed by 6 h reperfusion | To assess the role of PI3K/AKT pathway in hepatic I/R injury, LY294002 pretreatment abolished the protective effect of rmGas6 and exacerbated ferroptosis | Transplantation. 2024 Nov 1;108(11):e357-e369. |
Clinical Trial:
| NCT Number | Conditions | Phases | Recruitment | Completion Date | Locations |
| NCT02337309 | Neuroblastoma | Phase 1 | Terminated(Low patient accrual... More >>) Less << | - | United States, California ... More >> Children's Hospital Los Angeles Los Angeles, California, United States, 90027-0700 UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California, United States, 94143 United States, Colorado Children Hospital of Colorado Aurora, Colorado, United States, 80045 United States, Georgia AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus Atlanta, Georgia, United States, 30322 United States, Illinois University of Chicago Comer Children's Hospital Chicago, Illinois, United States, 60637 United States, Massachusetts Childrens Hospital Boston, Dana-Farber Cancer Institute. Boston, Massachusetts, United States, 02115 United States, Michigan C.S Mott Children's Hospital Ann Arbor, Michigan, United States, 48109 United States, North Carolina University of North Carolina Chapel Hill, North Carolina, United States, 27599 United States, Ohio Cincinnati Children's Hospital Medical Center Cincinnati, Ohio, United States, 45229-3039 United States, Texas Cook Children's Healthcare System Fort Worth, Texas, United States, 76104 United States, Washington Children's Hospital and Regional Medical Center - Seattle Seattle, Washington, United States, 98105 Less << |
| Bio Calculators | ||||
| Preparing Stock Solutions | ![]() |
1mg | 5mg | 10mg |
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1 mM 5 mM 10 mM |
3.25mL 0.65mL 0.33mL |
16.27mL 3.25mL 1.63mL |
32.54mL 6.51mL 3.25mL |
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