Delving into the Latest Updates on Copper Gluconate/Disulfiram with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

DSF-Cu, Dicopp, Disulfiram/copper gluconate

+ [2]

Target

ADHs

Action

inhibitors

Mechanism

ADHs inhibitors(Alcohol dehydrogenases inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesSkin and Musculoskeletal Diseases+ [1]

Active Indication

Breast CancerGlioblastomaGlioblastoma Multiforme

Inactive Indication

Liver CancerMetastatic castration-resistant prostate cancerMetastatic Pancreatic Cancer+ [2]

Originator Organization

CANTEX, Inc.

Active Organization

Washington University School of Medicine

CANTEX, Inc.

Inactive Organization

Cantex Pharmaceuticals, Inc.

University of Utah

License Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC12H22CuO14

InChIKeyOCUCCJIRFHNWBP-IYEMJOQQSA-L

CAS Registry527-09-3

View All Structures (2)

This is a phase I, open-label trial of disulfiram in combination with copper gluconate in patients with treatment-refractory multiple myeloma. The trial is designed to assess the Phase 2 Recommended Dose (RP2D) of disulfiram and copper gluconate in combination. The trial will open with dose escalation, followed to an expansion cohort to further characterize the safety and tolerance of the combination.
Dose escalation will utilize a standard 3+3 design and will test up to five dose levels. Dose levels will be separated into two sequential parts defined by the fixed dose of copper as copper gluconate administered with ascending doses of disulfiram. Part 1 of dose escalation will consist of dose levels 0 and 1 with the option to reduce to Dose Level -1 if Dose Level 0 is deemed intolerable. Part 2 will test dose levels 2 and 3. The Dose Level deemed to be the RP2D will be used in dose expansion.

Start Date21 May 2021

Sponsor / Collaborator

University of Utah

[+1]

NCT03714555

/ TerminatedPhase 2IIT

A Phase II Pilot Study of Disulfiram and Copper Gluconate in Patients With Metastatic Pancreatic Cancer and Rising CA-19-9 Levels While Receiving Abraxane-Gemcitabine or FOLFIRINOX or Single-Agent Gemcitabine

This is an open-label Phase 2 Pilot study to evaluate Disulfiram + Copper Gluconate in patients metastatic pancreatic cancer whose CA-19-9 levels rise while receiving nab-paclitaxel (Abraxane) plus gemcitabine (Gemzar) or FOLFIRINOX or single-agent gemcitabine (Gemzar). Patient must have received a minimum of 8 weeks of treatment and have rising CA-19-9 levels in the absence of radiographic evidence of progression.

Start Date17 Oct 2019

Sponsor / Collaborator

HonorHealth Ambulatory

[+1]

100 Clinical Results associated with Copper Gluconate/Disulfiram

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100 Translational Medicine associated with Copper Gluconate/Disulfiram

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100 Patents (Medical) associated with Copper Gluconate/Disulfiram

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36

Literatures (Medical) associated with Copper Gluconate/Disulfiram

01 Dec 2024·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Disulfiram/copper complex improves the effectiveness of the WEE1 inhibitor Adavosertib in p53 deficient non-small cell lung cancer via ferroptosis

Article

Author: Su, Bo ; Liu, Di ; Xu, Yaping ; Shi, Minxing ; Tai, Qidong ; Yao, Xiaojuan ; Dai, Mengyuan ; Ding, Xi ; Fei, Ke ; Cao, Jingxue ; Xu, Wen

Cancer cells lacking functional p53 exhibit poor prognosis, necessitating effective treatment strategies. Inhibiting WEE1, the G2/M cell cycle checkpoint gatekeeper, represents a promising approach for treating p53-deficient NSCLC. Here, we investigate the connection between p53 and WEE1, as well as explore a synergistic therapeutic approach for managing p53-deficient NSCLC. Our study reveals that p53 deficiency upregulates both protein levels and kinase activity of WEE1 by inhibiting its SUMOylation process, thereby enhancing the susceptibility of p53-deficient NSCLC to WEE1 inhibitors. Furthermore, we demonstrate that the WEE1 inhibitor Adavosertib induces intracellular lipid peroxidation, specifically in p53-deficient NSCLC cells, suggesting potential synergy with pro-oxidant reagents. Repurposing Disulfiram (DSF), an alcoholism medication used in combination with copper (Cu), exhibits pro-oxidant properties against NSCLC. The levels of WEE1 protein in p53-deficient NSCLC cells treated with DSF-Cu exhibit a time-dependent increase. Subsequent evaluation of the combination therapy involving Adavosertib and DSF-Cu reveals reduced cell viability along with smaller tumor volumes and lighter tumor weights observed in both p53-deficient cells and xenograft models while correlating with solute carrier family 7-member 11 (SLC7A11)/glutathione-regulated ferroptosis pathway activation. In conclusion, our findings elucidate the molecular interplay between p53 and WEE1 and unveil a novel synergistic therapeutic strategy for treating p53-deficient NSCLC.

25 Sep 2024·Current Cancer Drug Targets

Disulfiram-Copper Potentiates Anticancer Efficacy of Standard Chemo-therapy Drugs in Bladder Cancer Animal Model through ROS-Autophagy-Ferroptosis Signalling Cascade

Article

Author: Panwar, Ritika ; Rastogi, Pulkit ; Kakkar, Ashish ; Konar, Monidipa ; Kumar, Sandeep ; Singh, Sheetal ; Mavuduru, Ravimohan S. ; Dey, Sumit ; Naithani, Priyanka ; Sharma, Neeru ; Pattanaik, Smita

Background:Cost-effective management of Urinary Bladder Cancer (UBC) is an unmet needAims:Our study aims to demonstrate the efficacy of a drug repurposing strategy by using disulfiram (DSF) and copper gluconate (Cu) as an add-on treatment combination to traditional GC-based chemother-apy against N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced UBC mice (C57J) model.Methods:Male C57BL/6J mice were given 0.05% BBN in drinking water ad libitum, and tumour for-mation was verified by histological and physical evaluation. Animals were subsequently divided into eight groups and received treatment with different drug combinations. Control animals received only ve-hicle (DMSO). At the end of the treatment schedule, the bladder tumour was excised and further used to check the expression (mRNA and protein) of ALDH1 isoenzymes using qRT-PCR, western blot, and IHC methods. Autophagy induction was assessed by quantifying the expression of LC3B and SQSTM1/p62 proteins through IHC. Biochemical analysis of superoxide dismutase (SOD), reduced glutathione (GSH), and lipid peroxidation levels in the freshly isolated tumours was performed to check the alterations in the antioxidant system caused by combination treatment.Results:We observed significant induction of an invasive form of bladder cancer in the mice after nine-teen weeks of BBN exposure. The animals began exhibiting early indications of inflammatory alterations as early as the sixth week following BBN treatment. Furthermore, the wet bladder weight and overall tu-mour burden were significantly decreased (p< 0.0001) by DSF-Cu co-treatment in addition to the GC-based chemotherapy. Real-time PCR analysis revealed that treatment with disulfiram and copper glu-conate significantly decreased (p<0.0001) the mRNA expression of ALDH1 isoenzymes. Comparing the triple drug combination group (GC+DSF-Cu) to the untreated mice, a significant rise in LC3B puncta (p<0.0001) and a decrease in P62/SQSTM1 (p=0.0002) were noted, indicating the induction of autophagy flux in the add-on group. When GC+DSF-Cu treated mice were compared to the untreated tumour group, a substantial decrease in ALDH1/2 protein expression was observed (p= 0.0029 in IHC and p<0.0001 in western blot). Lipid peroxidation was significantly higher (p<0.0001) in the triple drug combination group than in untreated mice. There was a simultaneous decrease in reduced glutathione (GSH) and en-zyme superoxide dismutase (SOD) levels (p<0.0001), which strongly suggests the generation of reactive oxygen species and induction of ferroptotic cell death in the add-on therapy group. Additionally, in both IHC and western blot assays, ALDH1A3 expression was found to be significantly increased (p=0.0033, <0.0001 respectively) in GC+DSF-Cu treated mice relative to the untreated group, suggesting a potential connection between the ferroptosis pathway and ALDH1A3 overexpression.Conclusion:It was found that disulfiram with copper treatment inhibits bladder tumour growth through ferroptosis-mediated ROS induction, which further activates the process of autophagy. Our results prove that DSF-Cu can be an effective add-on therapy along with the standard chemotherapy drugs for the treatment of UBC.

01 Jul 2024·Biomedicine & Pharmacotherapy

The combination therapy using tyrosine kinase receptors inhibitors and repurposed drugs to target patient-derived glioblastoma stem cells

Article

Author: Lisiak, Natalia ; Pospieszna, Julia ; Rubis, Blazej ; Tang, Jing ; Kucinska, Malgorzata ; Murias, Marek ; Toton, Ewa

The lesson from many studies investigating the efficacy of targeted therapy in glioblastoma (GBM) showed that a future perspective should be focused on combining multiple target treatments. Our research aimed to assess the efficacy of drug combinations against glioblastoma stem cells (GSCs). Patient-derived cells U3042, U3009, and U3039 were obtained from the Human Glioblastoma Cell Culture resource. Additionally, the study was conducted on a GBM commercial U251 cell line. Gene expression analysis related to receptor tyrosine kinases (RTKs), stem cell markers and genes associated with significant molecular targets was performed, and selected proteins encoded by these genes were assessed using the immunofluorescence and flow cytometry methods. The cytotoxicity studies were preceded by analyzing the expression of specific proteins that serve as targets for selected drugs. The cytotoxicity study using the MTS assay was conducted to evaluate the effects of selected drugs/candidates in monotherapy and combinations. The most cytotoxic compounds for U3042 cells were Disulfiram combined with Copper gluconate (DSF/Cu), Dacomitinib, and Foretinib with IC₅₀ values of 52.37 nM, 4.38 µM, and 4.54 µM after 24 h incubation, respectively. Interactions were assessed using SynergyFinder Plus software. The analysis enabled the identification of the most effective drug combinations against patient-derived GSCs. Our findings indicate that the most promising drug combinations are Dacomitinib and Foretinib, Dacomitinib and DSF/Cu, and Foretinib and AZD3759. Since most tested combinations have not been previously examined against glioblastoma stem-like cells, these results can shed new light on designing the therapeutic approach to target the GSC population.

1

News (Medical) associated with Copper Gluconate/Disulfiram

14 Sep 2021

·www.biospace.com

Cantex Pharmaceuticals Announces Sale of Equity Interest in Chimerix, Inc.

WESTON, Fla., Sept. 14, 2021 /PRNewswire/ -- Cantex Pharmaceuticals ("Cantex") today announced that it has sold 6.5 million shares of Chimerix, Inc., in brokerage transactions at a price of $5.75 per share, less brokerage commissions and fees. About Cantex Pharmaceuticals Cantex Pharmaceuticals, Inc. is a privately-held, clinical stage pharmaceutical company focused on the transformation of known drugs into innovative products with blockbuster potential. Cantex is currently developing novel cancer treatments. Cantex's pipeline consists of three product candidates in Phase 2 and Phase 3 development for diseases with significant unmet medical needs: Azeliragon for life-threatening and disabling complications of cancer, Dicopp® for hematologic malignancies, and DSTAT, licensed to Chimerix, Inc., as a first-line therapy of acute myeloid leukemia. For more information, please visit . Cantex Contacts Investors: Stephen G. Marcus, M.D. (954) 315-3660 smarcus@cantex.com or Media: Jason Rando Tiberend Strategic Advisors (917) 930-6346 jrando@tiberend.com

100 Deals associated with Copper Gluconate/Disulfiram

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma Multiforme	Phase 2	United States	Washington University School of Medicine	15 Jun 2016
Breast Cancer	Phase 2	-	CANTEX, Inc.	-
Glioblastoma	Phase 2	-	CANTEX, Inc.	-
Refractory Multiple Myeloma	Discovery	United States	Cantex Pharmaceuticals, Inc.	21 May 2021
Metastatic Pancreatic Cancer	Discovery	United States	Cantex Pharmaceuticals, Inc.	17 Oct 2019
Metastatic castration-resistant prostate cancer	Discovery	United States	Cantex Pharmaceuticals, Inc.	11 Jul 2017
Recurrent Glioblastoma	Discovery	United States	Cantex Pharmaceuticals, Inc.	09 Mar 2017
Liver Cancer	Discovery	United States	University of Utah	01 Jul 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02715609 (TITE-CRM, CTgov)	Phase 1/2	Glioblastoma Multiforme	35	Radiation+Temozolomide+Disulfiram (Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion))	hhurrdkisa(zjorwzthsx) = agtwpouoef qlgaindktb (zbhgaksvxh, nkaagmldkj - zxhivptfkq) View more	-	10 Apr 2025
				Radiation+Temozolomide+Disulfiram (Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2))	(hcmdxmeqlf) = rxxtpububa ofnhvsimbk (sxcdluwtcn, ikchqwdmtz - pxwafjzdhp) View more
NCT03714555 (CTgov)	Phase 2	Metastatic Pancreatic Cancer	1	AE Assessment+nab-paclitaxel (Abraxane)+Disulfiram/Copper Gluconate+gemcitabine (Gemzar) (Nab-Paclitaxel/Gemcitabine + DSF/Cu)	wmzerpidvz(ufmeryhgsc) = ybrfiazist pvfrvrmlmw (rurbgarukv, npjrlvxkdo - foxpsecezc) View more	-	18 Oct 2023
				AE Assessment+nab-paclitaxel (Abraxane)+Disulfiram/Copper Gluconate+gemcitabine (Gemzar) (FOLFIRINOX +DSF/Cu)	wmzerpidvz(ufmeryhgsc) = hpxkuzgqnp pvfrvrmlmw (rurbgarukv, lwlqagccrg - qrfawssocz) View more
NCT03034135 (ACTR-21, CTgov)	Phase 2	Recurrent Glioblastoma	23	Temozolomide (TMZ)+Disulfiram/Copper	(hspgluvasc) = snvevqnsyg tfwgtgnwpu (nkalqzgyqe, wwvawraoro - plcigmfftt) View more	-	13 Sep 2021
EXTH-61 (SNO2020)	Not Applicable	Recurrent Medulloblastoma ALDH \| Nestin- \| CD133-positive	-	Disulfiram	xqcfclnuih(jksrpahovp) = DSF/Cu++ induced cell death (increased AnnV/PI, cleaved-Poly(ADP-ribose)polymerase fraction, and Apoptosis Inducing Factor on WB/FC/IF, in vitro and ex vivo) through NPL4 accumulation in cell nucleus and intracellular buildup of poly-ubiquitylated proteins epgmbhnzwq (weihjwkffj ) View more	Positive	09 Nov 2020
				Copper
PDTM-06 (SNO2019)	Not Applicable	Medulloblastoma	24	Disulfiram-Copper (DSF-Cu++)	iwsruhczgi(ewnqejopfr) = iktcnmwnri zcatnpfidk (ehnofpfbcr )	Positive	11 Nov 2019
				Disulfiram-Copper (Control (No treatment))	iwsruhczgi(ewnqejopfr) = bcwxirzyyk zcatnpfidk (ehnofpfbcr )