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DRUG:

RG4733

i
Other names: R4733, RG4733, RO4929097
Company:
Roche
Drug class:
Notch inhibitor
2ms
Screening of differential gene expression patterns through survival analysis for diagnosis, prognosis and therapies of clear cell renal cell carcinoma. (PubMed, PLoS One)
Then we detected 10 repurposable drug molecules (Irinotecan, Imatinib, Telaglenastat, Olaparib, RG-4733, Sorafenib, Sitravatinib, Cabozantinib, Abemaciclib, and Dovitinib.) by molecular docking with KGs-mediated receptor proteins. Their ADME/T analysis and cross-validation with the independent receptors, also supported their potent against ccRCC. Therefore, these outputs might be useful inputs/resources to the wet-lab researchers and clinicians for considering an effective treatment strategy against ccRCC.
Journal • PARP Biomarker
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CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • SERPINA5 (Serpin Family A Member 5)
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Lynparza (olaparib) • sorafenib • imatinib • Verzenio (abemaciclib) • Cabometyx (cabozantinib tablet) • irinotecan • dovitinib (TKI258) • telaglenastat (CB-839) • sitravatinib (MGCD516) • RG4733
12ms
CLL Cells within the Proliferation Centers of the Patient Lymph Nodes Are Enriched for Notch Signaling, Thus NOTCH a Viable Target for CLL Therapy (ASH 2023)
Therefore, as a next logical step we treated the MEC-1 and OSU-CLL cells in culture and primary CLL cell from patients with NOTCH inhibitor RO4929097 (RO), a γ-secretase inhibitor for 24, 48 and 72 hours in vitro...This work was partially supported by bridge funding from the American Association of Hematology awarded to Dr. Runqing Lu, who passed away during the pursuit of this study.
Clinical
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NOTCH1 (Notch 1) • BTK (Bruton Tyrosine Kinase) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • NOTCH2 (Notch 2) • IRF4 (Interferon regulatory factor 4) • NEDD4 (NEDD4 E3 Ubiquitin Protein Ligase)
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NOTCH1 expression • IRF4 expression
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RG4733
almost1year
The E2F1/MELTF axis fosters the progression of lung adenocarcinoma by regulating the Notch signaling pathway. (PubMed, Mutat Res)
Together, our outcomes demonstrated that E2F1 fostered LUAD progression by activating MELTF via the Notch signaling activity. Hence, MELTF emerged as a feasible target for treating LUAD.
Journal
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NOTCH1 (Notch 1) • MELTF (Melanotransferrin) • HES1 (Hes Family BHLH Transcription Factor 1) • E2F1 (E2F transcription factor 1)
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NOTCH1 expression • MELTF expression • MFI2 expression
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RG4733
over1year
Cdk4 Regulates Glioblastoma Cell Invasion and Stemness and Is Target of a Notch Inhibitor Plus Resveratrol Combined Treatment. (PubMed, Int J Mol Sci)
In this study, we found that in GBM cells, treatment with low toxicity doses of the γ-secretase inhibitor RO4929097 (GSI), blocking the Notch pathway activity, in combination with resveratrol (RSV) was able to reverse the basal mesenchymal phenotype to an epithelial-like phenotype, affecting invasion and stemness interplay...The exogenous expression of a constitutively active Cdk4 mutant prevented the RSV + GSI inhibitory effects in GBM cell motility/invasion and augmented the expression of stemness-specific markers, as well as the neurosphere sizes/forming abilities in untreated cells. In conclusion, we propose that Cdk4 is an important regulator of GBM stem-like phenotypes and invasive capacity, highlighting how the combined treatment of Notch inhibitors and RSV could be prospectively implemented in the novel therapeutic strategies to target Cdk4 for these aggressive brain tumors.
Journal
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CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4) • VCL (Vinculin)
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CDK4 mutation
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RG4733
over1year
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
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STAT3 (Signal Transducer And Activator Of Transcription 3)
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cisplatin • Jakafi (ruxolitinib) • RG4733 • tofacitinib • LY-411575
over2years
Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma. (PubMed, PeerJ)
Consequently, NEDD4L negatively regulated Notch signaling activation in LUAD cells, and RO4929097 (a Notch inhibitor) treatment effectively repressed the effect of NEDD4L knockdown on LUAD cell proliferation. Taken together, these results demonstrate that down-regulated NEDD4L facilitates LUAD progression by activating Notch signaling, and NEDD4L may be a promising target to treat LUAD.
Journal
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NOTCH2 (Notch 2)
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RG4733
over2years
Numb-PRRL promotes TGF-β1- and EGF-induced epithelial-to-mesenchymal transition in pancreatic cancer. (PubMed, Cell Death Dis)
Numb-PRRL overexpression activated TGFβ1-Smad2/3-Snail1 signaling was significantly reversed by the Notch1 inhibitor RO4929097...In vivo, Numb-PRRL overexpression or silencing promoted or inhibited subcutaneous tumor size and distant liver metastases via regulating EMT and Snail signaling, respectively. Numb-PRRL promotes TGF-β1- and EGF-induced EMT in PC by regulating TGF-β1-Smad2/3-Snail and EGF-induced EGFR-ERK/MAPK signaling.
Journal
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NOTCH1 (Notch 1) • CDH1 (Cadherin 1) • VIM (Vimentin) • TGFB1 (Transforming Growth Factor Beta 1) • CDH2 (Cadherin 2) • SNAI1 (Snail Family Transcriptional Repressor 1) • SNAI2 (Snail Family Transcriptional Repressor 2)
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CDH1 expression • VIM expression
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RG4733
over2years
A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC). (PubMed, Clin Breast Cancer)
In animal models of endocrine-resistant breast cancer, combinations of tamoxifen and GSIs produce additive or synergistic efficacy, while decreasing the intestinal toxicity of GSIs. Ten patients with evaluable archival tissue showed expression of PKCα, which correlated with expression of Notch4. Mammospheres from a PKCα-expressing, endocrine-resistant T47D cell line were inhibited by a GSI-fulvestrant combination Our data indicate that combinations including endocrine therapy and Notch inhibitors deserve further investigation in endocrine-resistant ERα-positive breast cancer.
Clinical • P1 data • Journal • Combination therapy
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ER (Estrogen receptor) • NOTCH4 (Notch 4)
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ER positive
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tamoxifen • fulvestrant • exemestane • RG4733
almost3years
A Notch inhibitor plus Resveratrol induced blockade of autophagy drives glioblastoma cell death by promoting a switch to apoptosis. (PubMed, Am J Cancer Res)
We used low doses of the γ-secretase inhibitor RO4929097 (GSI), to block the Notch pathway activity, in combination with Resveratrol (RSV) and we evidenced the mechanisms of autophagy/apoptosis transition in GBM cells...In short, we establish the role of CDK4 in the regulation of autophagy/apoptosis transition induced by RSV and GSI in GBM cells. This new synergistic therapeutic combination, increasing the accumulation of autophagosomes, may have therapeutic value for GBM patients.
Journal • PARP Biomarker
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CDK4 (Cyclin-dependent kinase 4) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • CASP3 (Caspase 3) • CASP8 (Caspase 8) • CASP9 (Caspase 9)
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CDK4 mutation
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RG4733
almost3years
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.
Review • Journal
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TNFRSF10B (TNF Receptor Superfamily Member 10b)
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RG4733 • LY-411575 • MK-0752
almost3years
Human umbilical vein endothelial cells derived-exosomes promote osteosarcoma cell stemness by activating Notch signaling pathway. (PubMed, Bioengineered)
Human osteosarcoma cells (U2OS and 143B) were treated with HUVECs supernatant, HUVECs-exosomes with or without RO4929097 (γ secretase inhibitor, used to block Notch signaling pathway)...In conclusion, this work demonstrated that HUVECs-exosomes promoted cell stemness in osteosarcoma through activating Notch signaling pathway. Thus, our data reveals the mechanism of HUVECs-exosomes in regulating cell stemness of osteosarcoma, and provides a theoretical basis for osteosarcoma treatment by exosomes.
Journal
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • NOTCH1 (Notch 1) • SOX2 • POU5F1 (POU Class 5 Homeobox 1) • HES1 (Hes Family BHLH Transcription Factor 1)
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NOTCH1 expression • POU5F1 expression
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RG4733
over3years
γ-secretase inhibitors, DAPT and RO4929097, promote the migration of Human Glioma Cells via Smad5-downregulated E-cadherin Expression. (PubMed, Int J Med Sci)
These results help further elucidate the molecular mechanisms of γ-secretase activity regulation involved in controlling glioma cell malignancy. Information about a potential role for Smad1/5 activity upregulation and subsequent E-cadherin downregulation during inhibition of γ-secretase activity in the development of gliomas is therefore relevant for future research.
Journal
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CDH1 (Cadherin 1)
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CDH1 expression
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RG4733
over3years
Systematic Evaluation for the Influences of the SOX17/Notch Receptor Family Members on Reversing Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells. (PubMed, Front Oncol)
The γ secretase inhibitors, BMS-708163, GSI-IX, PF-3084014, and RO4929097 abrogated the enzalutamide resistance by inhibiting Notch1 or/and Notch4 in vitro, with GSI-IX and RO4929097 being more effective than BMS-708163 and PF-3084014 in reliving bone metastasis in vivo. In conclusion, the Notch1 and Notch4 inhibitors GSI-IX and RO4929097 are promising therapeutic agents for the treatment of CRPC.
Journal
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NOTCH1 (Notch 1) • NOTCH4 (Notch 4) • SOX17 (SRY-Box Transcription Factor 17)
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Xtandi (enzalutamide capsule) • Ogsiveo (nirogacestat) • RG4733
4years
Notch3 is involved in the proliferation of renal cancer cells via regulation of cell cycle progression and HIF-2α. (PubMed, Oncol Lett)
Following transfection of the vector containing the NICD3 coding sequence, HIF-2α, CDK4, cyclin D1 and proliferating cell nuclear antigen expression, that were inhibited by RO4929097 in hypoxia, were rescued. Collectively, the results of the present study suggest that Notch3 is closely associated with the cell proliferation of ccRCC cells by regulating the cell cycle and HIF-2α.
Journal
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CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4) • NOTCH3 (Notch Receptor 3) • PCNA (Proliferating cell nuclear antigen)
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CCND1 expression • NOTCH3 expression • PCNA expression
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RG4733
over4years
Loss of Notch1 activity inhibits prostate cancer growth and metastasis and sensitizes prostate cancer cells to anti-androgen therapies. (PubMed, Mol Cancer Ther)
Therapeutic inhibition of Notch1 activity with gamma secretase inhibitors RO4929097 or DAPT in prostate cancer cells further results in decreased proliferative abilities. Combination of gamma secretase inhibitors with Abiraterone significantly inhibited cell migration and invasion, while combination with Enzalutamide reversed Enzalutamide induced migration and invasion. These collective findings suggest loss of Notch1 delays growth of CRPC, inhibits metastasis, and inhibition of Notch1 activation in conjunction with second-generation anti-androgen therapies could delay growth and progression of prostate cancer.
Journal
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NOTCH1 (Notch 1)
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Xtandi (enzalutamide capsule) • abiraterone acetate • RG4733
over4years
Targeting Nuclear NOTCH2 by Gliotoxin Recovers a Tumor-Suppressor NOTCH3 Activity in CLL. (PubMed, Cells)
We compared the anti-neoplastic effects of the nuclear NOTCH2 inhibitor gliotoxin and the pan-NOTCH γ-secretase inhibitor RO4929097 in primary CLL cells with special emphasis on the individual roles of the different NOTCH receptors...This was accompanied by a gain in accessibility at the NR4A1, NFκB, and ATF3 motifs close to the genes involved in B-cell activation, differentiation, and apoptosis. In summary, these data show that gliotoxin recovers a non-canonical tumor-suppressing NOTCH3 activity, indicating that nuclear NOTCH2 inhibitors might be beneficial compared to pan-NOTCH inhibitors in the treatment of CLL.
Journal
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NOTCH2 (Notch 2) • NOTCH3 (Notch Receptor 3)
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NOTCH3 expression
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RG4733
over4years
Reciprocal Regulation Between Indoleamine 2,3-Dioxigenase 1 and Notch1 Involved in Radiation Response of Cervical Cancer Stem Cells. (PubMed, Cancers (Basel))
The radiosensitivity of HeLa and SiHa tumorsphere cells was increased after the inhibition of IDO1 through RNA interference or by the treatment of INCB-024360, an IDO1 inhibitor...The inhibition of Notch1 by shRNA downregulated IDO1 expression in cervical CSCs and the binding of the intracellular domain of Notch (NICD) on the IDO1 promoter was reduced by Ro-4929097, a γ-secretase inhibitor...Furthermore, kynurenine increased the tumorsphere formation capability and the expression of cancer stemness genes including Oct4 and Sox2. Our data provide a reciprocal regulation mechanism between IDO1 and Notch1 expression in cervical cancer cells and suggest that the IDO1 inhibitors may potentially be used as radiosensitizers.
Journal
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NOTCH1 (Notch 1) • SOX2 • AHR (Aryl hydrocarbon receptor)
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IDO1 expression
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epacadostat (INCB024360) • RG4733
almost5years
Antiproliferative and Immunoregulatory Effects of Azelaic Acid Against Acute Myeloid Leukemia via the Activation of Notch Signaling Pathway. (PubMed, Front Pharmacol)
Moreover, combining AZA with the Notch inhibitor, RO4929097, decreased the expression of Notch1and Notch2, and downstream HES1 and HEY1, which rendered AML cells insensitive to AZA-induced apoptosis and alleviated AZA-mediated cytotoxicity in AML...The percentage of CD3CD56NK cells and CD4CD8T cells as well as the secretion of cytotoxic cytokines was increased after the treatment of AZA. The overall findings reveal that AZA is a potential Notch agonist against AML in activating the Notch signaling pathway.
Journal
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NOTCH2 (Notch 2) • IL2RA (Interleukin 2 receptor, alpha) • HES1 (Hes Family BHLH Transcription Factor 1)
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RG4733