PG-545(PG-545) - 药物靶点：HPSE_专利_临床

概要

基本信息

药物类型

化学药

别名

Pixatimod

靶点

HPSE

作用机制

乙酰肝素酶抑制剂、血管生成抑制剂

治疗领域

肿瘤消化系统疾病呼吸系统疾病+ [3]

在研适应症-

非在研适应症

晚期恶性实体瘤乳腺癌结直肠癌+ [5]

原研机构

TBG Diagnostics Ltd.

在研机构-

非在研机构

基亚生物科技股份有限公司Zucero Therapeutics Pty Ltd.

Progen Pharmaceuticals, Inc.

+ [1]

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C51H88NaO60S13

InChIKeyRPAUSRYLSBRVEA-PLSSCWMPSA-N

CAS号1144492-69-2

关联

5

项与 PG-545 相关的临床试验

NCT05061017 / Completed临床2期IIT

Phase IIA Basket Study of Pixatimod (PG545) in Combination With Nivolumab in PD-1 Relapsed/Refractory Metastatic Melanoma and NSCLC and Pixatimod (PG545) in Combination With Nivolumab and Low-dose Cyclophosphamide in MSS Metastatic Colorectal Carcinoma (mCRC)

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.

开始日期2021-12-09

申办/合作机构

University of Pittsburgh

ACTRN12617001573347 / Completed临床1期

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

开始日期2017-10-24

申办/合作机构

SCIENTIA CLINICAL RESEARCH LIMITED初创企业

NCT02042781 / Completed临床1期

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.

开始日期2014-01-01

申办/合作机构

Zucero Therapeutics Pty Ltd.

100 项与 PG-545 相关的临床结果

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100 项与 PG-545 相关的转化医学

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100 项与 PG-545 相关的专利（医药）

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48

项与 PG-545 相关的文献（医药）

2024-09-01·Journal of Cellular and Molecular Medicine

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

Article

作者: 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.

2023-09-01·Oncogene

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

Article

作者: 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.

2023-01-01·Pharmacology

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

Article

作者: 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 项与 PG-545 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
非小细胞肺癌	临床2期	美国	Zucero Therapeutics Pty Ltd.	2021-11-14
黑色素瘤	临床2期	美国	Zucero Therapeutics Pty Ltd.	2021-10-24
结直肠癌	临床2期	美国	Zucero Therapeutics Pty Ltd.	2021-10-10
胰腺癌	临床2期	澳大利亚	-	2017-10-23
晚期恶性实体瘤	临床2期	澳大利亚	Zucero Therapeutics Pty Ltd.	2011-01-01
乳腺癌	临床2期	澳大利亚	Progen Pharmaceuticals, Inc.	-
肝癌	临床2期	-	基亚生物科技股份有限公司	-
卵巢癌	临床2期	澳大利亚	Progen Pharmaceuticals, Inc.	-
卵巢癌	临床2期	澳大利亚	Progen Pharmaceuticals, Inc.	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ACTRN12617001573347 (SITC2021)	临床1期	转移性胰腺腺癌 \| 晚期恶性实体瘤 CA19.9 \| interleukins (IL) IL-1Î± \| IL-23	16	Pixatimod 25 mg	壓鏇觸顧襯製膚築製製(糧構遞願構鹽糧顧網築) = 蓋鑰顧蓋範遞鬱獵顧餘膚廠網鬱鹽壓積廠醖鑰 (壓觸蓋衊繭鏇窪鹹艱壓 )	不佳	2021-11-10
				Pixatimod 50 mg	壓鏇觸顧襯製膚築製製(糧構遞願構鹽糧顧網築) = 鹽鹽夢鬱夢壓廠獵襯製膚廠網鬱鹽壓積廠醖鑰 (壓觸蓋衊繭鏇窪鹹艱壓 )
NCT02042781 (ASCO2017)	临床1期	HR阳性/HER2低表达实体瘤	23	PG545	(壓憲顧衊窪齋選製壓遞) = 觸積網構選糧築顧廠襯鏇鏇構襯廠鑰積簾鬱廠 (襯遞蓋衊願艱製鑰夢襯 ) 更多	-	2017-05-30
NCT01252095 (CTgov)	临床1期	晚期恶性实体瘤	4	PG545 (25 mg Dose)	鏇顧膚選積糧網鹽觸範(鏇選顧鑰選衊窪鬱糧構) = 簾願鹽廠鬱齋鹹衊網範簾鏇鏇積壓積範衊繭簾 (網夢簾選艱獵夢鏇艱鹽, 壓憲膚製鏇鏇鏇鏇衊簾 ~ 範襯壓簾繭齋餘壓憲積) 更多	-	2012-08-02
				PG545 (50 mg Dose)	鏇顧膚選積糧網鹽觸範(鏇選顧鑰選衊窪鬱糧構) = 襯餘選獵淵選築鏇壓鑰簾鏇鏇積壓積範衊繭簾 (網夢簾選艱獵夢鏇艱鹽, 廠網鑰憲餘膚觸鬱範衊 ~ 遞夢繭糧願築繭構築鹹) 更多