Delving into the Latest Updates on Sepantronium Bromide with Synapse

Background:
Carboplatin-paclitaxel is a commonly used chemotherapy combination for advanced non-small-cell lung carcinoma (NSCLC) and other solid tumors. In a randomized clinical trial, the combination of carboplatin, paclitaxel, and the additional chemotherapy drug bevacizumab had a better response rate and survival compared to carboplatin and paclitaxel alone. However, this trial treated only patients with a specific diagnosis and treatment risks. Further research is needed to determine whether this combination is useful for other diagnoses.
YM155 is a drug that targets a type of chemical often found in cancer cells. It has been investigated in several phase I and phase II clinical trials, and it has been shown to be well tolerated and moderately effective in treating advanced NSCLC in patients who had not responded well to one or two standard treatments.
Objectives:
- To determine the efficacy of the combination of carboplatin, paclitaxel, and YM155 in the treatment of non-small-cell lung cancer.
Eligibility:
- Individuals 18 years of age and older who have been diagnosed with advanced non-small-cell lung carcinoma or other solid tumors for which standard therapy is not likely to be effective.
Design:
Before the start of the study, participants will be screened with a medical history, blood tests, imaging scans of the affected areas, tumor biopsies, and other tests as directed by the study doctors.
Participants will be treated for six 21-day cycles, or 18 weeks of treatment. Each cycle will include blood tests and imaging studies as required.
On day 1 of each cycle, participants will receive an infusion of paclitaxel and carboplatin, followed by a 4-day infusion of YM155 (through a portable electronic infusion pump).
Participants will have a computed tomography scan or other imaging every other cycle (approximately every 6 weeks) to determine whether the therapy is affecting the cancer site.
After the sixth cycle, participants will return for follow-up visits at least every 3 months, and will be asked to remain in contact with the researchers to allow further study of the long-term effects of the treatment.

Start Date01 Feb 2010

Sponsor / Collaborator

National Cancer Institute

NCT01038804 / CompletedPhase 2

A Phase II, Multicenter, Open-Label, Randomized Study of YM155 Plus Docetaxel as First-Line Treatment in Subjects With HER2 Negative Metastatic Breast Cancer

The purpose of this study is to evaluate survival, response rate, safety and tolerability of YM155 given in combination with docetaxel as first-line treatment in subjects with human epidermal growth factor 2 non-overexpressing (HER2 negative) metastatic breast cancer.

Start Date01 Dec 2009

Sponsor / Collaborator

Astellas Pharma, Inc.

100 Clinical Results associated with Sepantronium Bromide

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100 Translational Medicine associated with Sepantronium Bromide

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100 Patents (Medical) associated with Sepantronium Bromide

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346

Literatures (Medical) associated with Sepantronium Bromide

01 Nov 2024·Biochemical and Biophysical Research Communications

Integrated mRNA-seq and miRNA-seq analysis reveals key transcription factors of HNF4α and KLF4 in ADPKD

Article

Author: Zhang, Liming ; Yang, Bo ; Chen, Jiaxin ; Fu, Lili ; Mei, Shuqin ; Zhou, Chenchen ; Huang, Linxi ; Lu, Chunlai ; Mao, Zhiguo ; Xue, Cheng

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent genetic disorder affecting the kidneys. Understanding epigenetic regulatory mechanisms and the role of microRNAs (miRNAs) is crucial for developing therapeutic interventions. Two mRNA datasets (GSE7869 and GSE35831) and miRNA expression data (GSE133530) from ADPKD patients were used to find differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs), with a focus on genes regulated by hub transcription factors (TFs) and their target genes. The expression of hub TFs was validated in human kidneys and animal models through Western Blot (WB) and RT-PCR analysis. The location of the hub TF proteins in kidney cells was observed by a laser confocal microscope. A total of 2037 DEGs were identified. DEM analysis resulted in 59 up-regulated and 107 down-regulated miRNAs. Predicted target DEGs of DEMs indicated two top dysregulated TFs: hepatocyte nuclear factor 4 alpha (HNF4α) and Kruppel-like factor 4 (KLF4). RT-PCR, WB, and immunochemistry results showed that mRNA and protein levels of HNF4α were significantly decreased while KLF4 levels were significantly up-regulated in human ADPKD kidneys and Pkd1 conditional knockout mice compared with normal controls. Laser confocal microscopy revealed that KLF4 was mainly located in the cytoplasm while HNF4α was in the nucleus. Functional enrichment analysis indicated that genes regulated by HNF4α were mainly associated with metabolic pathways, while KLF4-regulated genes were linked to kidney development. Drug response prediction analysis revealed potential drug candidates for ADPKD treatment, including BI-2536, Sepantronium, and AZD5582. This integrated analysis provides new epigenetic insights into the complex miRNA-TF-mRNA network in ADPKD and identifies HNF4α and KLF4 as key TFs. These findings offer valuable resources for further research and potential drug development for ADPKD.

01 Sep 2024·Mitochondrion

SIRT6 suppresses colon cancer growth by inducing apoptosis and autophagy through transcriptionally down-regulating Survivin

Article

Author: Luo, Guang ; Li, Yanqiu ; Jiang, Meimei ; Liu, Nannan ; Liu, Chun ; Zhang, Yingjie ; Zhang, Lingling

SIRT6, an evolutionarily conserved histone deacetylase, has been identified as a novel direct downstream target of Akt/FoxO3a and a tumor suppressor in colon cancer in our previous research. Nevertheless, the precise mechanisms through which SIRT6 hinders tumor development remain unclear. To ascertain whether SIRT6 directly impacts Survivin transcription, a ChIP assay was conducted using an anti-SIRT6 antibody to isolate DNA. YM155 was synthesized to explore Survivin's role in mitochondrial apoptosis, autophagy and tumor progression. Our investigation into the regulation of Survivin involved real-time fluorescence imaging in living cells, real-time PCR, immunohistochemistry, flow cytometry, and xenograft mouse assays. In this current study, we delved into the role of SIRT6 in colon cancer and established that activated SIRT6 triggers mitochondrial apoptosis by reducing Survivin expression. Subsequent examinations revealed that SIRT6 directly binds to the Survivin promoter, impeding its transcription. Notably, direct inhibition of Survivin significantly impeded colon cancer proliferation by inducing mitochondrial apoptosis and autophagy both in vitro and in vivo. 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.

01 Sep 2024·Hematology, Transfusion and Cell Therapy

The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells

Article

Author: Lima, Keli ; Carlos, Jorge Antonio Elias Godoy ; Machado-Neto, João Agostinho ; Costa-Lotufo, Leticia Veras ; Rego, Eduardo Magalhães

The central role of the control of apoptosis in the pathophysiology of Philadelphia chromosome-negative myeloproliferative neoplasms has recently been reinforced in genetic and pharmacological studies. The inhibitor of apoptosis protein family has eight members and plays an important role in apoptosis, with the most studied being survivin (BIRC5) and X-linked inhibitor of apoptosis (XIAP). YM155 is a small molecule with antineoplastic potential that has been described as a suppressant of survivin and XIAP. In the present study, BIRC5 expression was significantly increased in primary myelofibrosis patients compared to healthy donors. On the other hand, XIAP expression was reduced in myeloproliferative neoplasms patients. In JAK2^V617F cells, YM155 reduces cell viability and autonomous clonal growth and induces apoptosis, cell cycle arrest, and autophagy. HEL cells that show greater malignancy are more sensitive to the drug than SET2 cells. In the molecular scenario, YM155 modulates apoptosis-, cell cycle-, DNA damage- and autophagy-related genes. 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 JAK2^V617F cells suggesting that inhibitor of apoptosis proteins may be a target for pharmacological interventions in the treatment of these diseases.

1

News (Medical) associated with Sepantronium Bromide

19 Dec 2022

·www.biospace.com

Cothera Announces Dosing of First Patient in Phase 2 Clinical Trial to Test Its DUB Inhibitor PC-002 for the Treatment of High-Grade B-cell Lymphoma

San Francisco, December 19, 2022--Cothera Bioscience today announced that it has dosed the first patient with PC-002, a first-in-class deubiquitinase (DUB) inhibitor, in a global multi-center phase 2 clinical trial for the treatment of high-grade B-cell lymphoma with Myc rearrangement (NCT05263583). This is a single-arm, single-agent proof-of-concept trial designed to evaluate PC-002 in patients who are either resistant or refractory to prior treatments. The company also announced that a paper1 describing PC-002’s mechanism-of-action was accepted for publication in the European Journal of Pharmaceutical Science. PC-002 (also known as YM155, sepantronium bromide) is a first-in-class small molecule inhibitor of DUB, an enzyme family which removes ubiquitin from cellular proteins otherwise destined for degradation. By inhibiting a key DUB activity that stabilizes the Myc protein in cancer cells, PC-002 selectively induces Myc protein degradation and cell apoptosis in Myc-dependent tumors. As Myc is regarded as one of the most important yet “undruggable” cancer targets with increased expression in more than 50% of human cancers, PC-002 may potentially address multiple cancer indications involving Myc dysregulation. Dr. Alex Wu, Co-founder and CEO of Cothera Bioscience, commented: "We are excited to dose the first patient in this important proof-of-concept trial. DUBs are an emerging target family with broad potential in cancer and inflammation treatment. PC-002 is the most advanced clinical stage DUB inhibitor which works by accelerating the degradation of Myc oncoprotein and has great potential to treat cancers depending on high Myc activity. Myc-driven high-grade lymphoma is a highly malignant, life-threatening disease for which there is currently no good treatment. We look forward to validating the safety and efficacy of PC-002 through this trial, providing a new solution for improving the prognosis of patients with this devastating disease, and delivering a breakthrough in the treatment of Myc-driven tumors.” 1. Li et al. YM155 Inhibits Neuroblastoma Growth through Degradation of MYCN: A New Role as a USP7 Inhibitor, European Journal of Pharmaceutical Sciences (2022) doi: About Cothera Bioscience, Inc. Cothera Bioscience is a clinical stage biotech company developing therapeutics for previously undruggable oncology targets with high unmet medical needs. The company’s strength is in its clinically validated translational platform exploiting synthetic lethality and protein degradation pathways for cancer killing. It was formed by the core founding members of Crown Bioscience, a leading contract research organization specializing in translational oncology, together with veteran serial entrepreneurs from Silicon Valley. Proprietary i-CR® technology platform Cothera Bioscience developed a patented proprietary i-CR® technology platform, a powerful method for individualized drug screening and new drug development. The platform combines a high content screening system with conditional reprogramming of primary cultured tumor cells, which enables efficient and undifferentiated expansion of primary patient-derived tumor cells in vitro while preserving the tumor’s heterogeneity. Through collaboration with leading oncology medical centers, Cothera Bioscience carried out prospective clinical trials and demonstrated that the i-CR® system can effectively predict the actual clinical response of a drug, with potential to significantly improve the clinical efficacy and success rate in anticancer drug development. (Transl Oncol. 2021 Jan;14(1):100935). For more information, please visit or send email to: bd@cotherabio.com

Phase 2

100 Deals associated with Sepantronium Bromide

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KEGG	Wiki	ATC	Drug Bank
D10164	-	-	-

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diffuse large B-cell lymphoma refractory	Phase 2	CA	Astellas Pharma, Inc.	01 Jun 2007
Diffuse large B-cell lymphoma refractory	Phase 2	ES	Astellas Pharma, Inc.	01 Jun 2007
Diffuse large B-cell lymphoma refractory	Phase 2	US	Astellas Pharma, Inc.	01 Jun 2007
Diffuse large B-cell lymphoma refractory	Phase 2	FR	Astellas Pharma, Inc.	01 Jun 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05263583 (ASH2023)	Phase 2	C-Myc positive High grade B-cell lymphoma	-	PC-002 (Sepantronium Bromide, or SepB)	(mmsdukmpyg) = kfytsliwpk krylgmsjbb (uhsechgmyn )	-	09 Dec 2023
NCT01007292 (Pubmed \| Leukemia) Manual	Phase 2	Aggressive B-Cell Non-Hodgkin Lymphoma	41	YM155+Rituximab	(rtuopwwyqi) = wazepokcrj ukgvrhyhsu (hdnmpmwjnn ) View more	Negative	01 Aug 2016
ASCO2016	Phase 1	EGFR-mutated non-small Cell Lung Cancer	18	YM155 + Erlotinib	qaiedcfgxy(qmiwghtvfu) = One patient receiving 4.8 mg/ m2/d Y developed a dose-limiting transient reversible grade 2 serum creatinine elevation lcwguatjmi (wjdjkawuyt ) View more	Positive	20 May 2016
NCT01009775 (Pubmed \| Cancer Med) Manual	Phase 2	Melanoma	64	docetaxel+YM155	(uhmhrblmph) = mgmndnuspk mymxsnjumr (anaslmcrtb, 21.3 - 48.6) View more	Negative	01 May 2015
NCT01100931 (Pubmed \| Ann Oncol)	Phase 1/2	Advanced Lung Non-Small Cell Carcinoma	42	Sepantronium Bromide	(lyfxnlxnkn) = vpglveamwn egxmtcrxxu (fjfbwvsibl ) View more	-	01 Oct 2013
NCT01038804 (ASCO2013) Manual	Phase 2	HER2-negative breast cancer First line HER2 negative	101	docetaxel+YM155	(vshoqlhtdx) = upapkmwmlo srzbarwmgr (sdujukapfg, 176 - 333) View more	Positive	20 May 2013
NCT01038804 (ASCO2013) Manual	Phase 2	HER2-negative breast cancer First line HER2 negative	101	docetaxel	(vshoqlhtdx) = lvsbemzehc srzbarwmgr (sdujukapfg, 202 - 433) View more	Positive	20 May 2013
ASCO2012	Phase 2	Melanoma	64	YM155 plus docetaxelYM155 plus docetaxel	(ihxjiigolj) = axpwmphogb byxagwkrwx (hnofyyefqi ) View more	Negative	20 May 2012
E1611 (ASCO2012)	Not Applicable	Merkel Cell Carcinoma	-	YM155	wlurspivrl(mahvhcszuy) = aubqbnpklw pxhyoaezoo (qlorzfzcmb )	-	20 May 2012
E1611 (ASCO2012)	Not Applicable	Merkel Cell Carcinoma	-	Bortezomib	wlurspivrl(mahvhcszuy) = pxacnxqtnz pxhyoaezoo (qlorzfzcmb )	-	20 May 2012
ASCO2011	Phase 1	Solid tumor	22	Paclitaxel	(pfjbbvlyrz) = spsdfledbz xioqmquwkv (gktmwnupok ) View more	-	20 May 2011
ASCO2011	Phase 1	Solid tumor	22	Carboplatin	(pfjbbvlyrz) = ibjvolxxmr xioqmquwkv (gktmwnupok ) View more	-	20 May 2011
ASCO2009	Not Applicable	Diffuse Large B-Cell Lymphoma	43	YM155	(wfjaujzlcw) = dwyhjqfthc nfqnrzkilo (xsaujydygf ) View more	-	20 May 2009