Delving into the Latest Updates on PG-545 with Synapse

Overview

Basic Info

Drug Type

Chemical drugs

Synonyms

Pixatimod

Target

HPSE

Mechanism

Heparanase inhibitors, Angiogenesis inhibitors

Therapeutic Areas

NeoplasmsDigestive System DisordersRespiratory Diseases+ [3]

Active Indication-

Inactive Indication

Advanced Malignant Solid NeoplasmBreast CancerColorectal Cancer+ [5]

Originator Organization

TBG Diagnostics Ltd.

Active Organization-

Inactive Organization

Medigen Biotechnology Corp.Zucero Therapeutics Pty Ltd.

Progen Pharmaceuticals, Inc.

+ [1]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC51H88NaO60S13

InChIKeyRPAUSRYLSBRVEA-PLSSCWMPSA-N

CAS Registry1144492-69-2

The primary goal of this trial is to assess clinical response to nivolumab and pixatimod, and, nivolumab, pixatimod and cyclophosphamide in three separate patient cohorts. Cohort 1: MSS mCRC in combination with low-dose cyclophosphamide, Cohort 2: PD-1 relapsed/refractory melanoma, and Cohort 3: PD-1 relapsed/refractory NSCLC.

Start Date09 Dec 2021

Sponsor / Collaborator

University of Pittsburgh

ACTRN12617001573347 / CompletedPhase 1

An open-label, multi-centre Phase Ib study of the safety and tolerability of IV infused PG545 in combination with nivolumab in patients with advanced solid tumours with an expansion cohort in patients with metastatic pancreatic cancer

Start Date24 Oct 2017

Sponsor / Collaborator

SCIENTIA CLINICAL RESEARCH LIMITEDStartup

NCT02042781 / CompletedPhase 1

An Open-label, Multi-centre Phase I Study of the Safety and Tolerability of IV Infused PG545 in Patients With Advanced Solid Tumours

This Phase Ia study aims to establish the maximum tolerated dose of once-weekly IV infused PG545 and to evaluate its safety in subjects with advanced solid tumours. In addition, the study will explore whether PG545 exposure results in changes to chemicals produced by the body that are associated with cancer growth and spread.

Start Date01 Jan 2014

Sponsor / Collaborator

Zucero Therapeutics Pty Ltd.

100 Clinical Results associated with PG-545

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100 Translational Medicine associated with PG-545

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100 Patents (Medical) associated with PG-545

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48

Literatures (Medical) associated with PG-545

01 Sep 2024·Journal of Cellular and Molecular Medicine

Involvement of heparanase in the pathogenesis of acute pancreatitis: Implication of novel therapeutic approaches

Article

Author: Hamo‐Giladi, Dalit B. ; Hamoud, Shadi ; Hadad, Salim ; Sabo, Edmond ; Fokra, Ahmad ; Abassi, Zaid ; Khamaysi, Iyad ; Kabala, Aviva ; Minkov, Irena

AbstractAcute pancreatitis (AP) is a common gastrointestinal disease with high morbidity and mortality rate. Unfortunately, neither the etiology nor the pathophysiology of AP are fully understood and causal treatment options are not available. Recently we demonstrated that heparanase (Hpa) is adversely involved in the pathogenesis of AP and inhibition of this enzyme ameliorates the manifestation of the disease. Moreover, a pioneer study demonstrated that Aspirin has partial inhibitory effect on Hpa. Another compound, which possesses a mild pancreato‐protective effect against AP, is Trehalose, a common disaccharide. We hypothesized that combination of Aspirin, Trehalose, PG545 (Pixatimod) and SST0001 (Roneparstat), specific inhibitors of Hpa, may exert pancreato‐protective effect better than each drug alone. Thus, the current study examines the pancreato‐protective effects of Aspirin, Trehalose, PG545 and SST0001 in experimental model of AP induced by cerulein in wild‐type (WT) and Hpa over‐expressing (Hpa‐Tg) mice. Cerulein‐induced AP in WT mice was associated with significant rises in the serum levels of lipase (X4) and amylase (X3) with enhancement of pancreatic edema index, inflammatory response, and autophagy. Responses to cerulein were all more profound in Hpa‐Tg mice versus WT mice, evident by X7 and X5 folds increase in lipase and amylase levels, respectively. Treatment with Aspirin or Trehalose alone and even more so in combination with PG545 or SST0001 were highly effective, restoring the serum level of lipase back to the basal level. Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti‐Hpa drug combinations constitute a novel therapy for this common orphan disease.

01 Sep 2023·Oncogene

PG545 sensitizes ovarian cancer cells to PARP inhibitors through modulation of RAD51-DEK interaction.

Article

Author: Block, Matthew S ; Dredge, Keith ; Shridhar, Viji ; Xiao, Yinan ; Bakkum-Gamez, Jamie N ; Hammond, Edward ; Thirusangu, Prabhu ; Kaufmann, Scott H ; Erskine, Courtney L ; Staub, Julie ; Jin, Ling ; Pathoulas, Christopher L ; Ray, Upasana

PG545 (Pixatimod) is a highly sulfated small molecule known for its ability to inhibit heparanase and disrupt signaling mediated by heparan-binding-growth factors (HB-GF). Previous studies indicated that PG545 inhibits growth factor-mediated signaling in ovarian cancer (OC) to enhance response to chemotherapy. Here we investigated the previously unidentified mechanisms by which PG545 induces DNA damage in OC cells and found that PG545 induces DNA single- and double-strand breaks, reduces RAD51 expression in an autophagy-dependent manner and inhibits homologous recombination repair (HRR). These changes accompanied the ability of PG545 to inhibit endocytosis of the heparan-sulfate proteoglycan interacting DNA repair protein, DEK, leading to DEK sequestration in the tumor microenvironment (TME) and loss of nuclear DEK needed for HRR. As a result, PG545 synergized with poly (ADP-ribose) polymerase inhibitors (PARPis) in OC cell lines in vitro and in 55% of primary cultures of patient-derived ascites samples ex vivo. Moreover, PG545/PARPi synergy was observed in OC cells exhibiting either de novo or acquired resistance to PARPi monotherapy. PG545 in combination with rucaparib also generated increased DNA damage, increased antitumor effects and increased survival of mice bearing HRR proficient OVCAR5 xenografts compared to monotherapy treatment in vivo. Synergistic antitumor activity of the PG545/rucaparib combination was likewise observed in an immunocompetent syngeneic ID8F3 OC model. Collectively, these results suggest that targeting DEK-HSPG interactions in the TME through the use of PG545 may be a novel method of inhibiting DNA repair and sensitizing cells to PARPis.

01 Jan 2023·Pharmacology

PG545 Prevents Osteoarthritis Development by Regulating PI3K/AKT/mTOR Signaling and Activating Chondrocyte Autophagy

Article

Author: Li, Xi ; Guo, Peiyu ; Wang, Xuming ; Li, Hua ; Li, Xingguo

Introduction: Osteoarthritis (OA) is a degenerative disease common in the elderly and is characterized by joint pain, swelling, and restricted movement. In recent years, heparanase has been reported to play an important role in the development of osteoarthritic cartilage. PG545 is a heparan sulfate mimetic with heparanase inhibitory activity. In this study, the therapeutic effects and possible mechanisms of PG545 were investigated in a chondrocyte injury model induced by interleukin-1β (IL -1β). Methods: Following treatment with PG545 or the autophagy inhibitor 3-methyladenine (3-MA), chondrocyte viability was detected using Cell Counting Kit-8 and fluorescein diacetate/propidium iodide double staining. The apoptosis rate of chondrocytes was determined by flow cytometry. Expression of light chain 3 and P62 was monitored by immunofluorescence labeling. Western blot, lentivirus infection with red fluorescent protein and green fluorescent protein, and quantitative real-time polymerase chain reaction were used to determine the expression levels of chondrocyte markers, apoptosis-related factors, autophagy proteins, and key proteins of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. The expression and activity of stress-specific enzymes such as malondialdehyde, superoxide dismutase, and catalase (CAT) were investigated. Chondrocytes with ATG5 knockdown were used to investigate the relationship between the therapeutic effect of PG545 and autophagy. The therapeutic effect of PG545 was verified in vivo. Results: PG545 had a significant protective effect on chondrocytes by reducing oxidative stress, apoptosis, and degradation of chondrocytes and increasing chondrocyte proliferation. PG545 was effective in inducing autophagy in IL-1β-treated cells, while 3-MA attenuated the effect. The PI3K/Akt/mTOR pathway may be involved in the promotion of autophagy and OA treatment by PG545. Conclusion: PG545 was able to restore impaired autophagy and autophagic flux via the PI3K/Akt/mTOR pathway, thereby delaying the progression of OA, suggesting that PG545 may be a novel therapeutic approach for OA.

100 Deals associated with PG-545

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Small Cell Lung Cancer	Phase 2	US	Zucero Therapeutics Pty Ltd.	14 Nov 2021
Melanoma	Phase 2	US	Zucero Therapeutics Pty Ltd.	24 Oct 2021
Colorectal Cancer	Phase 2	US	Zucero Therapeutics Pty Ltd.	10 Oct 2021
Pancreatic Cancer	Phase 2	AU	-	23 Oct 2017
Advanced Malignant Solid Neoplasm	Phase 2	AU	Zucero Therapeutics Pty Ltd.	01 Jan 2011
Breast Cancer	Phase 2	AU	Progen Pharmaceuticals, Inc.	-
Liver Cancer	Phase 2	-	Medigen Biotechnology Corp.	-
Ovarian Cancer	Phase 2	AU	Progen Pharmaceuticals, Inc.	-
Ovarian Cancer	Phase 2	AU	Progen Pharmaceuticals, Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ACTRN12617001573347 (SITC2021)	Phase 1	Pancreatic adenocarcinoma metastatic \| Advanced Malignant Solid Neoplasm CA19.9 \| interleukins (IL) IL-1Î± \| IL-23	16	Pixatimod 25 mg	yuglzbteml(vvnonwscmv) = pbsxpsexsm pyrkxvjsni (imwuyizozs )	Negative	10 Nov 2021
				Pixatimod 50 mg	yuglzbteml(vvnonwscmv) = basmzstpcn pyrkxvjsni (imwuyizozs )
NCT02042781 (ASCO2017)	Phase 1	HR-positive/HER2-low Solid Tumors	23	PG545	(qekhfdpkul) = xhtqzvvwuj yswhizchyv (ztdyxrsdws ) View more	-	30 May 2017
NCT01252095 (CTgov)	Phase 1	Advanced Malignant Solid Neoplasm	4	PG545 (25 mg Dose)	igpqtprpmz(ordkeyrrjq) = frgzevobzy rvnbleelbh (mjrffdpbzs, nzhunzygwe - gpogiudlre) View more	-	02 Aug 2012
				PG545 (50 mg Dose)	igpqtprpmz(ordkeyrrjq) = hxqmwvopht rvnbleelbh (mjrffdpbzs, agfmqcgupc - zcdclejkwo) View more