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DRUG:

sepantronium bromide (PC-002)

i
Other names: YM-155, YM 155, PC-002, YM155, SepB, PC 002, PC002
Company:
Astellas, Cothera Biosci
Drug class:
Survivin inhibitor
2ms
A Novel Porphyromonas gingivalis Infection-Related Inflammatory Response-Related Genes Signature Predicts the Prognosis of Esophageal Squamous Cell Carcinoma. (PubMed, Clin Med Insights Oncol)
A total of 41 drugs, including dactinomycin, luminespib, and sepantronium bromide, had a significant difference in IC50 between the 2 subgroups. We demonstrated the potential of a novel signature constructed from 4 P. gingivalis-related IRRGs for prognostic prediction in ESCC patients.
Journal
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DKK1 (dickkopf WNT signaling pathway inhibitor 1) • EREG (Epiregulin) • ESRRB (Estrogen Related Receptor Beta)
|
dactinomycin • luminespib (AUY922) • sepantronium bromide (PC-002)
2ms
The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells. (PubMed, Hematol Transfus Cell Ther)
Protein expression analysis corroborates the observed cellular phenotype and exploratory gene expression findings. In summary, our results indicate that survivin/BIRC5 and XIAP are differently expressed in myeloproliferative neoplasms and YM155 has multiple antineoplastic effects on JAK2V617F cells suggesting that inhibitor of apoptosis proteins may be a target for pharmacological interventions in the treatment of these diseases.
Journal
|
XIAP (X-Linked Inhibitor Of Apoptosis)
|
JAK2 V617F • BIRC5 expression
|
sepantronium bromide (PC-002)
4ms
SIRT6 suppresses colon cancer growth by inducing apoptosis and autophagy through transcriptionally down-regulating Survivin. (PubMed, Mitochondrion)
More interestingly, Survivin inhibition reactivated the Akt/FoxO3a pathway and elevated SIRT6 levels, establishing a positive feedback loop. Our results identify Survivin as a novel downstream transcriptional target of SIRT6 that fosters tumor growth and holds promise as a prospective target for colon cancer therapy.
Journal
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BIRC5 (Baculoviral IAP repeat containing 5) • SIRT6 (Sirtuin 6)
|
dactolisib (RTB101) • sepantronium bromide (PC-002)
6ms
Targeting mTOR and survivin concurrently potentiates radiation therapy in renal cell carcinoma by suppressing DNA damage repair and amplifying mitotic catastrophe. (PubMed, J Exp Clin Cancer Res)
Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.
Journal
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BIRC5 (Baculoviral IAP repeat containing 5)
|
everolimus • sepantronium bromide (PC-002)
7ms
ONC212 enhances YM155 cytotoxicity by triggering SLC35F2 expression and NOXA-dependent MCL1 degradation in acute myeloid leukemia cells. (PubMed, Biochem Pharmacol)
The continuous treatment of U937 cells with the benzene metabolite hydroquinone (HQ) generated U937/HQ cells, exhibiting enhanced responsiveness to the cytotoxic effects of ONC212...Collectively, our data suggested that ONC212 upregulated SLC35F2 expression and triggered NOXA-mediated MCL1 degradation in U937, U937/HQ, and HL-60 cells by activating the AKT/NOX4/HuR/ATF4 pathway. The ONC212-induced signaling pathway showed anti-AML activity and enhanced YM155 cytotoxicity.
Journal
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ATF4 (Activating Transcription Factor 4) • NOX4 (NADPH Oxidase 4)
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MCL1 expression
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ONC212 • sepantronium bromide (PC-002)
9ms
The SMAC mimetic GDC-0152 is a direct ABCB1-ATPase activity modulator and BIRC5 expression suppressor in cancer cells. (PubMed, Toxicol Appl Pharmacol)
Co-treatment with GDC-0152 restored the sensitivity to the known ABCB1 substrates, including paclitaxel, vincristine, and YM155 in ABCB1-expressing multidrug-resistant cancer cells, and it also restored the sensitivity to tamoxifen in BIRC5-overexpressing tamoxifen-resistant breast cancer cells in vitro...In conclusion, GDC-0152 has the potential for use in the management of cancer patients with ABCB1 and BIRC5-related drug resistance. The findings of our study provide essential information to physicians for designing a more patient-specific GDC-0152 clinical trial program in the future.
Journal
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ABCB1 (ATP Binding Cassette Subfamily B Member 1) • BIRC5 (Baculoviral IAP repeat containing 5)
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ABCB1 overexpression • ABCB1 expression • BIRC5 expression
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paclitaxel • tamoxifen • vincristine • sepantronium bromide (PC-002)
12ms
Synergistic cytotoxicity of decitabine and YM155 in leukemia cells through upregulation of SLC35F2 and suppression of MCL1 and survivin expression. (PubMed, Apoptosis)
Our data demonstrated that the synergistic cytotoxicity of DAC and YM155 in AML cell lines U937 and HL-60 is dependent on AKT- and p38 MAPK-mediated upregulation of SLC35F2 and p38 MAPK-mediated degradation of survivin and MCL1. This indicates that a treatment regimen that amalgamates YM155 and DAC may be beneficial for AML.
Journal
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MCL1 (Myeloid cell leukemia 1) • PMAIP1 (Phorbol-12-Myristate-13-Acetate-Induced Protein 1) • SP1 (Sp1 Transcription Factor)
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MCL1 expression • BIRC5 expression
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decitabine • sepantronium bromide (PC-002)
12ms
Single-Cell Multi-Ome Analysis Reveals Novel Molecular Mechanisms Underlying Subclonal Response to Survivin Inhibition in Relapsed/Refractory Multiple Myeloma (ASH 2023)
An earlier study has shown that YM155 enhances daratumumab-mediated cellular lysis of multiple myeloma cells. Our RNAseq and CyTOF results thus suggest a potential basis of synergy between YM155 with immunotherapies approved for myeloma, which we will test further. Our approach thus integrates in silico prediction with single-cell multi-ome analysis to identify molecular mechanisms potentially underlying subclonal response to novel combination therapy candidates (secDrugs) for the treatment of RRMM.
PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • BIRC5 (Baculoviral IAP repeat containing 5) • DDIT3 (DNA-damage-inducible transcript 3) • ATF3 (Activating Transcription Factor 3) • CD81 (CD81 Molecule)
|
MYC expression • BIRC5 expression
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Darzalex (daratumumab) • sepantronium bromide (PC-002)
1year
Treatment of Relapsed/Refractory Hgbcl and Bukitt's Lymphoma with c-Myc Rearrangement: A Multi-Center, Open-Label, Phase 2 Study of PC-002 (SepB), a First-in-Class Deubiquitinase Inhibitor Inducing Myc Degradation (ASH 2023)
PC-002 (also known as Sepantronium Bromide, or SepB) is a small molecule previously identified as a survivin suppressant with antitumor activity against a range of tumor types... At the time of abstract submission, the 1st cohort (3.6 mg/m2/day) of 3 patients have completed at least four cycles of treatment. PC-002 is generally well-tolerated at 3.6 mg/m2/day and progression to Cohort 2 at a dose of 4.8 mg/m2/ day was approved by the Safety Review Committee. Two patients with relapsed/refractory Burkitt Lymphoma at the starting dose of 3.6 mg/m2/day achieved a confirmed PR.
Clinical • P2 data
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BIRC5 (Baculoviral IAP repeat containing 5)
|
MYC rearrangement
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sepantronium bromide (PC-002)
over1year
PSMD3-ILF3 signaling cascade drives lung cancer cell proliferation and migration. (PubMed, Biol Direct)
PSMD3 collectively regulated the stability of ILF3 protein and facilitated the ubiquitination of endogenous ILF3 in LC, which ultimately promoted the progression of LC cells. The PSMD3/ ILF3 axis could potentially be used as a novel strategy for both diagnosis and treatment of LC.
Journal
|
sepantronium bromide (PC-002)
over1year
TREATMENT OF RELAPSED/REFRACTORY HGBCL WITH MYC REARRANGEMENT: A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY OF PC-002(SEPB),A FIRST-IN-CLASS INHIBITOR OF DEUBIQUITINASES TARGETING MYC DEGRADATION (EHA 2023)
PC-002 (also known as Sepantronium Bromide, SepB) is a small molecule survivin suppressant with antitumor activity against a variety of tumor types...At the time of abstract submission, the 1 st cohort of 3 patients have completed at least two cycles of dosing. PC- 002 is generally well-tolerated at 3.6 mg/m 2 /day and has been cleared by SRC to the next cohort of RP2D at 4.8 mg/m 2 / day. Preliminary assessment by image analysis showed partial response in 2 pts with relapsed/refractory Burkitt Lymphoma at the starting dose of 3.6 mg/m 2 /day.
Clinical • P2 data
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • BIRC5 (Baculoviral IAP repeat containing 5)
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MYC rearrangement
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sepantronium bromide (PC-002)
over1year
A Cell Type Selective YM155 Prodrug Targets Receptor-Interacting Protein Kinase 2 to Induce Brain Cancer Cell Death. (PubMed, J Am Chem Soc)
In addition, we determine that the survivin-suppressing and apoptosis-inducing activities of YM155 involve its interaction with receptor-interacting protein kinase 2 (RIPK2). In an orthotopic intracranial GBM xenograft model, aYM155 prodrug significantly inhibits brain tumor growth in vivo, which correlates with cell-type selective survivin-based pharmacodynamic effects.
Journal
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EGFR (Epidermal growth factor receptor) • RIPK2 (Receptor Interacting Serine/Threonine Kinase 2)
|
EGFR amplification • EGFR expression • BIRC5 expression • EGFRvIII expression
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sepantronium bromide (PC-002)
over1year
Oncogenic RAS promotes MYC protein stability by upregulating the expression of the inhibitor of apoptosis protein (IAP) family member Survivin. (PubMed, J Biol Chem)
This discovery stemmed from our finding that Survivin expression is downregulated upon treatment of pancreatic cancer cells with the KRAS inhibitor Sotorasib...CIP2A, by inhibiting protein phosphatase 2A (PP2A), helps to maintain MYC phosphorylation at Ser 62, thereby ensuring its cooperation with oncogenic KRAS in driving cancer progression. Overall, these findings highlight a novel role for Survivin in mediating the cooperative actions of KRAS and MYC during malignant transformation and raise the possibility that targeting Survivin may offer therapeutic benefits against KRAS-driven cancers.
Journal
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KRAS (KRAS proto-oncogene GTPase) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BIRC5 (Baculoviral IAP repeat containing 5)
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KRAS mutation • MYC expression • BIRC5 expression • KRAS expression
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Lumakras (sotorasib) • sepantronium bromide (PC-002)
almost2years
Sepantronium Bromide for the Treatment of High-grade B-cell Lymphoma (clinicaltrials.gov)
P2, N=18, Recruiting, Cothera Bioscience, Inc | Not yet recruiting --> Recruiting | Initiation date: Mar 2022 --> Dec 2022
Enrollment open • Trial initiation date
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2)
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sepantronium bromide (PC-002)
almost2years
YM155 Inhibits Neuroblastoma Growth through Degradation of MYCN: A New Role as a USP7 Inhibitor. (PubMed, Eur J Pharm Sci)
Our data reveal a novel mechanism of action of YM155 in cancer cells. YM155 has potential as a therapeutic agent in the treatment of MNA neuroblastoma, and MYCN status is a selection biomarker for sensitivity to YM155.
Journal
|
MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • USP7 (Ubiquitin Specific Peptidase 7)
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MYCN amplification
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sepantronium bromide (PC-002)
2years
Exploring MicroRNA and Exosome Involvement in Malignant Pleural Mesothelioma Drug Response. (PubMed, Cancers (Basel))
This effect was more pronounced for FAK (PND-1186) small molecule inhibitor treatment; consistent with previously published data. Additionally, our study showed no evidence of a correlation between the mRNA expression of inhibitor of apoptosis (IAP) gene family members and MPM cell sensitivity to YM155. However, two drug transporter genes, ABCA6 and ABCA10, were upregulated in the MPM cell lines and correlated with poor sensitivity to YM155.
Journal
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ABCA1 (ATP Binding Cassette Subfamily A Member 1)
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BIRC5 expression
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VS-4718 • sepantronium bromide (PC-002)
2years
Nutlin-3 Promotes TRAIL-Induced Liver Cancer Cells Apoptosis by Activating p53 to Inhibit bcl-2 and Surviving Expression. (PubMed, Ann Clin Lab Sci)
These results suggested that Nutlin-3 facilitated TRAIL-induced apoptosis of HCC cells by activating the p53-survivin/bcl-2 pathway, which provided novel insights into the mechanism of Nutlin-3 and confirmed the potential of combination of Nutlin-3 and TRAIL as an adjuvant in HCC therapy.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • TNFA (Tumor Necrosis Factor-Alpha) • CASP3 (Caspase 3) • CASP9 (Caspase 9) • CASP7 (Caspase 7)
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BCL2 expression • TP53 expression • BIRC5 expression
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Nutlin-3 • sepantronium bromide (PC-002)
2years
YM155 and chrysin cooperatively suppress survivin expression in SMARCB1/INI1-deficient tumor cells. (PubMed, Med Oncol)
Survivin is suggested to be a therapeutic target in MRT and other SMARCB1/INI1-deficient tumors. Chrysin, a flavone that is widely distributed in plants, cooperatively suppressed survivin expression and enhanced the cytotoxicity of YM155.
Journal
|
SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1)
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BIRC5 expression
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sepantronium bromide (PC-002)
over2years
Bone morphogenetic protein inhibitors and mitochondria targeting agents synergistically induce apoptosis-inducing factor (AIF) caspase-independent cell death in lung cancer cells. (PubMed, Cell Commun Signal)
These studies demonstrate that inhibition of BMP signaling together with mitochondrial targeting agents induce AIF caspase-independent cell death, which involves the "hyperactivation" of AMPK. AIF caspase-independent cell death is an evolutionarily conserved cell death pathway that is infrequently studied in cancer. These studies provide novel insight into mechanisms inducing AIF caspase-independent cell death in cancer cells using BMP inhibitors. Video Abstract.
Journal
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STK11 (Serine/threonine kinase 11)
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sepantronium bromide (PC-002)
over2years
Docetaxel-induced downregulation of Survivin sensitizes metastatic prostate cancer to platinum-based treatment (EACR 2022)
Interestingly, treatment with YM155 sensitized DU145 and PC3 cells to cisplatin and carboplatin exposure. Conclusion Our findings showed that Survivin is markedly reduced in docetaxel-exposed mCRPC preclinical models and suggest that Survivin expression levels might predict therapeutic response to platinum-based treatment in taxane-resistant mCRPC patients.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BIRC5 (Baculoviral IAP repeat containing 5) • CXCR2 (Chemokine (C-X-C motif) receptor 2)
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BIRC5 expression
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cisplatin • carboplatin • docetaxel • sepantronium bromide (PC-002)
over2years
Dandelion Seed Extract Affects Tumor Progression and Enhances the Sensitivity of Cisplatin in Esophageal Squamous Cell Carcinoma. (PubMed, Front Pharmacol)
In addition, survivin plays a critical role in DSE against ESCC followed with the application of survivin inhibitor YM155 impairing the inhibitory abilities of DSE in ESCC cells. Meanwhile, it was observed that DSE enhances the sensitivity of DDP to human ESCC cells via promoting DNA damage and inhibiting phosphorylation of STAT3. Therefore, DSE may affect ESCC progression and enhance the sensitivity of cisplatin, and consequently become an effective anti-cancer option for human ESCC treatment.
Journal
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BCL2 (B-cell CLL/lymphoma 2) • MLH1 (MutL homolog 1) • MSH2 (MutS Homolog 2) • ERCC1 (Excision repair cross-complementation group 1) • CDH1 (Cadherin 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • MMP2 (Matrix metallopeptidase 2) • CASP3 (Caspase 3) • VIM (Vimentin) • MMP9 (Matrix metallopeptidase 9) • PI3K (Phosphoinositide 3-kinases)
|
cisplatin • sepantronium bromide (PC-002)
over2years
YM155 induces DNA damage and cell death in anaplastic thyroid cancer cells by inhibiting DNA topoisomerase IIα at the ATP binding site. (PubMed, Mol Cancer Ther)
A Top2α mutant abrogates the effect of YM155, confirming the contribution of Top2α to YM155 mechanism of action. Our results suggest a novel mechanism of action for YM155 and may represent a new therapeutic approach for the treatment of anaplastic thyroid cancer.
Journal
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TOP2A (DNA topoisomerase 2-alpha)
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TOP2A overexpression • BIRC5 expression
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sepantronium bromide (PC-002)
over2years
Targeting inhibitor of apoptosis proteins (IAPs) with IAP inhibitors sensitises malignant rhabdoid tumour cells to cisplatin. (PubMed, Cancer Treat Res Commun)
In the present study, sensitivity of this same panel of MRT cell lines to small-molecule mediated inhibition of the IAPs via the survivin inhibitor YM155 and the XIAP/cIAP1/cIAP2 inhibitor BV6 was demonstrated. Importantly, we have demonstrated, for the first time, expression of XIAP, its target caspase-3 and its endogenous inhibitor SMAC in rhabdoid tumour patient tissue. In conclusion, this study provides pre-clinical evidence that IAP inhibition may be a new therapeutic option in MRT.
Journal
|
BIRC3 (Baculoviral IAP repeat containing 3) • CASP3 (Caspase 3) • XIAP (X-Linked Inhibitor Of Apoptosis)
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cisplatin • sepantronium bromide (PC-002)
over2years
Utilizing Three-Dimensional Culture Methods to Improve High-Throughput Drug Screening in Anaplastic Thyroid Carcinoma. (PubMed, Cancers (Basel))
Although combination dabrafenib/trametinib therapy was recently approved for treatment of the ~25% of ATCs harboring BRAFV600E mutations, there are no approved, effective treatments for BRAF-wildtype disease. These three-dimensional cultures include four distinct ATC spheroid lines representing unique morphology and mutational drivers to provide drug prioritization that will be more readily translatable to the clinic. Using this screen, we identify three exceptionally potent compounds (bortezomib, cabazitaxel, and YM155) that have established safety profiles and could potentially be moved into clinical trial for the treatment of anaplastic thyroid carcinoma, a disease with few treatment options.
Journal
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BRAF (B-raf proto-oncogene)
|
BRAF V600E • BRAF V600 • BRAF wild-type
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Mekinist (trametinib) • Tafinlar (dabrafenib) • bortezomib • cabazitaxel • sepantronium bromide (PC-002)
over2years
Bone morphogenetic protein receptor inhibitors suppress the growth of glioblastoma cells. (PubMed, Mol Cell Biochem)
We utilized BMP inhibitors DMH1, JL5, and Ym155 to examine the role of BMP signaling on the growth of GBMs...The lysosome inhibitor chloroquine increases the localization of BMPR2 to the plasma membrane enhancing JL5-induced downregulation of ID1 and cell death in SD2 cells. We show that BMP signaling is growth promoting in GBMs. These studies suggest the need for development of BMP inhibitors and evaluation as potential therapeutic for GBMs.
Journal
|
XIAP (X-Linked Inhibitor Of Apoptosis)
|
sepantronium bromide (PC-002) • chloroquine phosphate
over2years
Therapeutic efficacy of YM155 to repress an epigenetic enzyme and everolimus resistance in RCC. (AUA 2022)
Also, we suggested YM155 as a novel drug to overcome everolimus resistance. Therefore, this study will shed light on the therapy of various cancers that have everolimus resistance as well as RCCs.
Clinical
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AURKA (Aurora kinase A)
|
everolimus • sepantronium bromide (PC-002)
over2years
miRNA‑218 targets multiple oncogenes and is a therapeutic target for osteosarcoma. (PubMed, Oncol Rep)
In the animal model, both the miR‑218 and YM155 groups showed a reduced tumor volume and decreased survivin expression. In osteosarcoma, miR‑218 showed a wider range of therapeutic efficacy compared with YM155, suggesting that miR‑218 should be evaluated as a treatment target.
Journal
|
MIR218 (MicroRNA 218)
|
BIRC5 expression • miR‐218 overexpression
|
sepantronium bromide (PC-002)
over2years
New P2 trial
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2)
|
sepantronium bromide (PC-002)
almost3years
High ETV6 Levels Support Aggressive B Lymphoma Cell Survival and Predict Poor Outcome in Diffuse Large B-Cell Lymphoma Patients. (PubMed, Cancers (Basel))
Furthermore, an inverse correlation between ETV6 and BIRC5 expression levels was found and correlated with a response to the BIRC5 inhibitor, YM155. In conclusion, we present evidence for an oncogenic function of ETV6 in DLBCL.
Journal • PD(L)-1 Biomarker • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • PD-1 (Programmed cell death 1) • ETV6 (ETS Variant Transcription Factor 6) • PD-L2 (Programmed Cell Death 1 Ligand 2)
|
BIRC5 expression
|
sepantronium bromide (PC-002)
almost3years
AATF is Overexpressed in Human Bladder Cancer and Regulates Chemo-Sensitivity Through Survivin. (PubMed, Onco Targets Ther)
The decreased cisplatin sensitivity/apoptosis induced by ectopic AATF were reversed after treatment with Survivin inhibitor YM155. Our results showed that AATF was overexpressed in human bladder cancers and promoted malignant behavior by regulating cyclin E and Survivin, indicating AATF could serve as a malignant biomarker and potential therapeutic target in BC.
Journal • PARP Biomarker
|
BIRC5 (Baculoviral IAP repeat containing 5)
|
cisplatin • sepantronium bromide (PC-002)
almost3years
Hypoxia represses early responses of prostate and renal cancer cells to YM155 independent of HIF-1α and HIF-2α. (PubMed, Curr Res Pharmacol Drug Discov)
Moreover, the hypoxia mimetics deferoxamine and dimethyloxalylglycine, which robustly induce HIF-1α levels in PC-3 ​cells under atmospheric oxygen, did not diminish their early cellular responses to YM155. Collectively, our data support that hypoxia induces resistance of cells to YM155 through a HIF-1α and HIF-2α-independent mechanism. We hypothesize that a hypothetical hypoxia-inducer factor (HIF-X) represses early signaling responses to YM155.
Journal
|
MCL1 (Myeloid cell leukemia 1) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • EPAS1 (Endothelial PAS domain protein 1)
|
MCL1 expression • BIRC5 expression • HIF1A expression
|
sepantronium bromide (PC-002)
almost3years
Two-color fluorescent proteins reporting survivin regulation in breast cancer cells for high throughput drug screening. (PubMed, Biotechnol Bioeng)
This 3D dual-fluorescent reporter assay was validated with YM155 and doxorubicin, which were known to downregulate survivin in cancer cells, and further evaluated with two widely used anticancer compounds, cisplatin and epigallocatechin gallate, to evaluate their effects on survivin expression. This 3D dual-fluorescent reporter assay was validated with YM155 and doxorubicin, which were known to downregulate survivin in cancer cells, and further evaluated with two widely used anticancer compounds, cisplatin and epigallocatechin gallate, to evaluate their effects on survivin expression. The results showed that the 3D dual-fluorescent reporter assay was robust for high throughput screening of drugs targeting survivin in breast cancer cells.
Journal
|
BIRC5 (Baculoviral IAP repeat containing 5)
|
BIRC5 expression
|
cisplatin • doxorubicin hydrochloride • sepantronium bromide (PC-002)
almost3years
Identification and Validation of Afatinib Potential Drug Resistance Gene BIRC5 in Non-Small Cell Lung Cancer. (PubMed, Front Oncol)
In addition, overexpression of BIRC5 protein was detected in afatinib-resistant cells by western blot, while BIRC5-expressing cells treated with BIRC5 inhibitor, YM155, were sensitive to afatinib. In this study, we showed that overexpression of BIRC5 resulted in resistance to afatinib in NSCLC and BIRC5-specific inhibitors may overcome the resistant phenotype, indicating that dysregulation of the apoptotic cell death pathway may be the key mechanism underlying TKI resistance in the development of NSCLC.
Journal
|
EGFR (Epidermal growth factor receptor) • BIRC5 (Baculoviral IAP repeat containing 5)
|
BIRC5 expression • BIRC5 overexpression
|
Gilotrif (afatinib) • sepantronium bromide (PC-002)
3years
In silico Prediction Followed By In Vitro validation Identifies a Survivin Inhibitor and an MCL-1 Inhibitor As a Potent Secondary Drug Against Refractory or Relapsed Mantle Cell Lymphoma (ASH 2021)
Combination therapies such as R-CHOP, R-DHAP, Hyper-CVAD, VcR-CAP constitute the front-line chemotherapeutic treatment landscape for MCL...Our results showed that the YM155 and S63845 exhibited significant synergistic cell killing activities (Combination index/ CI value of 0.31±0.49 as calculated using Chou-Talalay's CI theorem, C.I>1 depicts synergism) alone and in combination with Bortezomib (PI) and Ibrutinib (BTKi), especially in R/R MCL cell lines...As both YM155 and S63845 have reported activity against cancer stem-ness, we will further investigate the effect of our novel drugs on the cancer stem-like cells in MCL, which have a potential role in treatment resistance. The secDrug algorithm promises to serve as a universal prototype for the discovery of novel drug combination regimens for treatment outcomes in any cancer type by enhancing sensitivity or overcoming resistance to standard of care drugs.
Preclinical
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BIRC5 (Baculoviral IAP repeat containing 5)
|
BIRC5 expression
|
Imbruvica (ibrutinib) • Rituxan (rituximab) • bortezomib • S63845 • sepantronium bromide (PC-002)
3years
A Predictive Endothelial-Leukemia Pre-Clinical Platform to Uncover Drug Vulnerabilities for Personalized Treatments (ASH 2021)
We found that ECs counteracted the activity of selected compounds (i.e. TSA, THZ1 and MLN2238)...Remarkably, IGFBP-7 completely or partially abrogated the EC-mediated rescue of selected compounds [enzastaurin (PKC-β inhibitor), SC144 (GP130 inhibitor), CHIR124 (Chk1 inhibitor) and YM155 (Survivin inhibitor)] (Figure 1B). Drugs not rescued by ECs (n=30) were considered positive hits and 5 of them (ruxolitinib, tofacitinib, panobinostat, bortezomib, irinotecan) ultimately proved to be effective in vivo in randomized pre-clinical trials either alone or in combination (Figure 1C)...These data demonstrate that our EC-T-ALL culture system simulates in vivo conditions, offering a robust platform to study drug response, leukemia-host interactions and cell plasticity. This approach will improve the pre-clinical predictability of novel drugs/combinations for T-ALL, as well as for other hematologic malignancies, and propel the development of patient-tailored treatments.
Preclinical
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IGF1 (Insulin-like growth factor 1) • IGFBP7 (Insulin Like Growth Factor Binding Protein 7) • PRKCB (Protein Kinase C Beta)
|
bortezomib • Jakafi (ruxolitinib) • irinotecan • Ninlaro (ixazomib) • Farydak (panobinostat) • Kinenza (enzastaurin) • sepantronium bromide (PC-002) • tofacitinib
over3years
Identification of subgroups along the glycolysis-cholesterol synthesis axis and the development of an associated prognostic risk model. (PubMed, Hum Genomics)
Subtyping SKCM patients via glycolytic and cholesterogenic genes was effective, and patients in the glycolytic-gene enriched group were found to have the worst outcome. A robust prognostic algorithm was developed to enhance clinical decisions in relation to drug administration.
Journal
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MGAM (Maltase-Glucoamylase) • DDR2 (Discoidin domain receptor 2)
|
Istodax (romidepsin) • sepantronium bromide (PC-002) • vindesine
over3years
KRAS-dependent cancer cells promote survival by producing exosomes enriched in Survivin. (PubMed, Cancer Lett)
Moreover, they significantly compromised the effectiveness of the conventional chemotherapy drug paclitaxel, as well as a novel therapy that combines an ERK inhibitor with chloroquine, which is currently in clinical trials for PDAC. The survival benefits provided by oncogenic KRAS-derived exosomes were markedly reduced when depleted of Survivin using siRNA or upon treatment with the Survivin inhibitor YM155. Taken together, these findings demonstrate how KRAS mutations give rise to exosomes that provide a unique form of intercellular communication to promote cancer cell survival and therapy resistance, as well as raise interesting possibilities regarding their potential for serving as therapeutic targets and diagnostic markers for KRAS-dependent cancers.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • BIRC5 (Baculoviral IAP repeat containing 5)
|
KRAS mutation
|
paclitaxel • sepantronium bromide (PC-002) • chloroquine phosphate
over3years
Dehydroabietic Acid Is a Novel Survivin Inhibitor for Gastric Cancer. (PubMed, Plants (Basel))
In addition, the ability of DAA to inhibit survivin was compared to that of YM-155, a known survivin inhibitor...DAA also caused an increase in cleaved caspase-3, an apoptosis-activating protein. In conclusion, DAA is a potential anticancer agent for gastric cancer that inhibits survivin expression.
Journal
|
BIRC5 (Baculoviral IAP repeat containing 5) • CASP3 (Caspase 3)
|
BIRC5 expression
|
sepantronium bromide (PC-002)
over3years
Clinical application of a lung cancer organoid (tumoroid) culture system. (PubMed, NPJ Precis Oncol)
Use of nutlin-3a was key to selecting lung tumoroids that harbor mutant p53 in order to eliminate normal lung epithelial organoids...Targeted therapies using small molecule drugs (trametinib/erlotinib for BRAF, crizotinib/entrectinib for TPM3-ROS1 and ABT-263/YM-155 for EGFR/RB1) significantly suppressed the growth of each lung tumoroid line. AO media was superior to 3 different media developed by other laboratories. Our experience indicates that long-term lung tumoroid culture is feasible, allowing us to identify NGS-based therapeutic targets and determine the responsiveness to corresponding small molecule drugs.
Journal
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EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • RB1 (RB Transcriptional Corepressor 1) • TPM3 (Tropomyosin 3)
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TP53 mutation
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Mekinist (trametinib) • Xalkori (crizotinib) • erlotinib • Rozlytrek (entrectinib) • navitoclax (ABT 263) • Nutlin-3 • sepantronium bromide (PC-002)