Delving into the Latest Updates on Muparfostat sodium with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Mannopentaose phosphate sulfate, Muparfostat, Muparfostat sodium (USAN)

+ [5]

Target

VEGF-A x aFGF x bFGF

Mechanism

VEGF-A inhibitors(Vascular endothelial growth factor A inhibitors), aFGF inhibitors(Fibroblast growth factor 1 inhibitors), bFGF inhibitors(Fibroblast growth factor 2 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System Disorders

Active Indication

HepatitisLiver Cancer

Inactive Indication

Advanced cancerAdvanced Lung Non-Small Cell CarcinomaCastration-Resistant Prostatic Cancer+ [10]

Originator Organization

Australian National University Library

Active Organization

Australian National University Library

Medigen Biotechnology Corp.

Inactive Organization

Progen Pharmaceuticals, Inc.

Drug Highest PhasePhase 3

First Approval Date-

RegulationOrphan Drug (US)

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BackgroundAmong women worldwide, breast cancer has the highest incidence and is the leading cause of cancer-related death. Patients with the triple-negative breast cancer (TNBC) subtype have an inferior prognosis in comparison to other breast cancers because current therapies do not facilitate long-lasting responses. Thus, there is a demand for more innovative therapies that induce durable responses.In our previous research, we discovered that augmenting the concentration of extracellular ATP (eATP) greatly enhances the chemotherapeutic response of TNBC cell lines by activating purinergic receptors (P2RXs), leading to cell death through the induction of non-selective membrane permeability. However, eATP levels are limited by several classes of extracellular ATPases. One endogenous molecule of interest that can inhibit multiple classes of extracellular ATPases is heparan sulfate. Polysulfated polysaccharide heparan sulfate itself is degraded by heparanase, an enzyme that is known to be highly expressed in various cancers, including breast cancer. Heparan sulfate has previously been shown to regulate several cancer-related processes such as fibroblast growth factor signaling, neoangiogenesis by sequestering vascular endothelial growth factors in the extracellular matrix, hedgehog signaling and cell adhesion. In this project, we identified an additional mechanism for a tumor suppressor role of heparan sulfate: inhibition of extracellular ATPases, leading to augmented levels of eATP.Several heparanase inhibitors have been previously identified, including OGT 2115, suramin, PI-88, and PG 545. We hypothesized that heparanase inhibitors would augment eATP concentrations in TNBC by increasing heparan sulfate in the tumor microenvironment, resulting in enhanced cell death in response to chemotherapy.MethodsWe treated TNBC cell lines MDA-MB 231, Hs 578t, and MDA-MB 468 and non-tumorigenic immortal mammary epithelial MCF-10A cells with increasing concentrations of the chemotherapeutic agent paclitaxel in the presence of heparan sulfate and/or the heparanase inhibitor OGT 2115 while analyzing eATP release and cell viability. Moreover, to verify that the effects of OGT 2115 are mediated through eATP, we applied specific antagonists to the purinergic receptors P2RX4 and P2RX7. In addition, the protein expression of heparanase was compared in the cell lines by Western blot analysis. We also evaluated the consequences of this therapeutic strategy on the breast cancer-initiating cell population in the treated cells using flow cytometry and tumorsphere formation efficiency assays.ResultsHeparanase was found to be highly expressed in immortal mammary epithelial cells in comparison to TNBC cell lines. The heparanase inhibitor OGT 2115 augmented chemotherapy-induced TNBC cell death and eATP release.ConclusionThese results demonstrate that inhibiting the degradation of heparan sulfate in the tumor microenvironment augments the susceptibility of TNBC cell lines to chemotherapy by increasing extracellular ATP concentrations. This strategy could potentially be applied to induce more enhanced and enduring responses in TNBC patients.

01 Jul 2023·British Journal of Pharmacology

The heparan sulfate mimetic Muparfostat aggravates steatohepatitis in obese mice due to its binding affinity to lipoprotein lipase

Article

Author: Sun, Shao‐Kun ; Sun, Hao‐Ran ; Zhou, Qin‐Yao ; Li, Guan‐Ting ; Li, Kai ; Sun, Peng ; Han, Xiao ; Ding, Ying ; Zhang, Jia ; Wu, Yu‐Xuan ; Ge, Yu‐Ting ; Zhu, Ya‐Ting ; Chang, Xiao‐Ai

Background and PurposeHeparanase is the only confirmed endoglycosidase that cleaves heparan sulfate (HS), a ubiquitous glycosaminoglycan with various essential roles in multiple pathological processes. Thus, the development of heparanase inhibitors has become an attractive strategy for drug discovery, especially in tumour therapy, in which HS mimetics are the most promising compounds. The various biological effects of heparanase also suggest a role for HS mimetics in many non‐cancer indications, such as type 1 diabetes. However, the potential benefits of HS mimetics in obesity‐related type 2 diabetes have not been elucidated.Experimental ApproachIn this study, we investigated muparfostat (PI‐88), a developed HS mimetic currently enrolled in Phase III clinical trials, in obese mouse models and in vitro cultured murine hepatocytes.Key ResultsDaily administration of muparfostat for 4 weeks caused hyperlipidaemia and aggravated hepatic steatosis in obese mice models, but not in lean animals. In cultured hepatocytes, muparfostat did not alter lipid accumulation. Acute tests suggested that muparfostat binds to lipoprotein lipase in competition with HS on vascular endothelial cell surfaces, thereby reducing the degradation of circulating triglycerides by lipoprotein lipase and subsequent uptake of fatty acids into vascular endothelial cells and causing hyperlipidaemia. This hyperlipidaemia aggravates hepatic steatosis and causes liver injury in muparfostat‐treated obese mice.Conclusions and ImplicationsThe binding activity of HS mimetics to lipoprotein lipase should be investigated as an additional pharmacological effect during heparanase inhibitor drug discovery. This study also provides novel evidence for an increased risk of drug‐induced liver injury in obese individuals.

01 Jun 2022·Carbohydrate ResearchQ4 · CHEMISTRY

Access to n-pentenyl tetra- and pentasaccharide analogues of the antitumor drug PI-88 based on 1,2-methyl orthoester glycosyl donors

Q4 · CHEMISTRY

Article

Author: López, J Cristobal ; Ventura, Juan ; Uriel, Clara ; Gómez, Ana M

Convergent synthetic routes to PI-88 tetra- and pentasaccharide-component analogues, have been developed featuring regioselective glycosylations of mannose-polyol n-pentenyl glycosides (NPG) acceptors with 1,2-methyl orthoesters (MeOE) glycosyl donors.

100 Deals associated with Muparfostat sodium

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External Link

KEGG	Wiki	ATC	Drug Bank
D10650	-	-	DB05808

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Liver Cancer	Phase 3	-	Australian National University Library	-
Primary Malignant Liver Neoplasm	Phase 1	US	Progen Pharmaceuticals, Inc.	01 Dec 2007
Primary Malignant Liver Neoplasm	Phase 1	ES	Progen Pharmaceuticals, Inc.	01 Dec 2007
Primary Malignant Liver Neoplasm	Phase 1	TH	Progen Pharmaceuticals, Inc.	01 Dec 2007
Primary Malignant Liver Neoplasm	Phase 1	TW	Progen Pharmaceuticals, Inc.	01 Dec 2007
Primary Malignant Liver Neoplasm	Phase 1	AU	Progen Pharmaceuticals, Inc.	01 Dec 2007
Primary Malignant Liver Neoplasm	Phase 1	CA	Progen Pharmaceuticals, Inc.	01 Dec 2007
Primary Malignant Liver Neoplasm	Phase 1	SG	Progen Pharmaceuticals, Inc.	01 Dec 2007
Primary Malignant Liver Neoplasm	Phase 1	MY	Progen Pharmaceuticals, Inc.	01 Dec 2007
Primary Malignant Liver Neoplasm	Phase 1	HK	Progen Pharmaceuticals, Inc.	01 Dec 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00130442 (CTgov)	Phase 2	Metastatic melanoma	134	dacarbazine+PI-88 (Arm 1- PI-88 Plus Dacarbazine)	ggptmygntb(klwodhcfup) = hpkpjzgwwv ybknmqzlua (aloteoyyih, uwlwcxnfud - wsbxpoytvj) View more	-	22 Jan 2021
				dacarbazine or DTIC (Arm 2- Dacarbazine Alone)	ggptmygntb(klwodhcfup) = ppuzxcgsrd ybknmqzlua (aloteoyyih, sdyntaxwlf - cfmogpxozk) View more
NCT01402908 (PATRON, CTgov)	Phase 3	Hepatitis B Virus-Related Hepatocellular Carcinoma	520	PI-88 (PI-88)	eebmkxzsmu(qwzdvbmvnd) = bcsgiztnvz jkpphmfzmc (bfuivhrhfs, czofopbnum - ajnggfkpxf) View more	-	30 Dec 2020
				Placebo (Placebo)	eebmkxzsmu(qwzdvbmvnd) = eohjnjhfyz jkpphmfzmc (bfuivhrhfs, kiaemmkpzu - hmlcpisixb) View more
NCT00247728 (Pubmed \| J Hepatol)	Phase 2	Hepatocellular Carcinoma Adjuvant	172	PI-88 (Untreated arm)	jeqprzljsw(fnlredhagm) = 1 (1.8%) group B patients and 6 (10.5%) group C had hepatotoxicity-related withdrawals cvmgunsvjg (uiwegzquzk )	-	01 May 2009
				PI-88 160 mg/day
ASCO2005	Phase 2	Melanoma	-	PI-88 250 mg/day	(afjplbortl) = sqbzepsole zgshfvmffg (ncggsibmgm ) View more	-	01 Jun 2005