Dopastatin(Dopastatin) - 药物靶点：D2 receptor x SSTR2 x SSTR5_专利_临床

概要

基本信息

药物类型

合成多肽

别名

靶点

D2 receptor x SSTR2 x SSTR5

作用机制

D2 receptor激动剂(多巴胺D2受体激动剂)、SSTR2激动剂(生长抑素受体2激动剂)、SSTR5激动剂(生长抑素受体5激动剂)

治疗领域

肿瘤神经系统疾病内分泌与代谢疾病+ [2]

在研适应症-

非在研适应症

肢端肥大症腺癌恶性类癌综合征+ [2]

原研机构

Ipsen SA

在研机构-

非在研机构

Ipsen SA

Tiburio Therapeutics, Inc.初创企业

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C86H116N16O12S4

InChIKeyWLBJBODHTIKYSL-JFPOTJHNSA-N

CAS号868562-36-1

序列信息

Sequence Code 525125508

关联

6

项与 Dopastatin 相关的临床试验

EUCTR2019-003142-32-HU / Not yet recruiting临床2期

A One Year, Randomized, Double-Blind, Placebo-Controlled Study of TBR-760 in Adult Patients with Non-Functioning Pituitary Adenomas

开始日期2020-07-08

申办/合作机构

Tiburio Therapeutics, Inc.初创企业

NCT04335357 / Unknown status临床2期

A One Year, Randomized, Double-Blind, Placebo-Controlled Study of TBR-760 in Adult Patients With Non-Functioning Pituitary Adenomas

This is a randomized, double-blind, placebo-controlled study to assess the safety, tolerability, efficacy, PK, and PD of the chimeric dopamine-somatostatin receptor agonist, TBR-760, in adult patients with NFPA over 52 weeks.

开始日期2020-05-01

申办/合作机构

Tiburio Therapeutics, Inc.初创企业

NCT01018953 / Terminated临床2期

Phase II, Open, Adaptive, Dose Escalating, Multicentre Titration Study to Assess the Efficacy and Safety of Repeated Subcutaneous Administration of Different Doses of BIM 23A760 in Patients With Carcinoid Syndrome

The purpose of the protocol is to assess the efficacy and safety of BIM 23A760 on patient's overall satisfaction in terms of symptom relief (diarrhoea and/or flushes) in patients with carcinoid syndrome after 24 weeks of treatment.

开始日期2010-02-01

申办/合作机构

Ipsen SA

100 项与 Dopastatin 相关的临床结果

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100 项与 Dopastatin 相关的转化医学

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100 项与 Dopastatin 相关的专利（医药）

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28

项与 Dopastatin 相关的文献（医药）

2021-06-01·Pituitary2区 · 医学

Characterization of the ability of a, second-generation SST-DA chimeric molecule, TBR-065, to suppress GH secretion from human GH-secreting adenoma cells

2区 · 医学

Article

作者: Cuny, Thomas ; Mougel, Grégory ; Graillon, Thomas ; Barlier, Anne ; Brue, Thierry ; Landsman, Tanya ; Halem, Heather A ; Zhang, Shengwen ; Defilles, Célines ; Culler, Michael D ; Datta, Rakesh ; Dufour, Henry ; Figarella-Branger, Dominique ; Saveanu, Alexandru

CONTEXTSomatostatin (SST) and dopamine (DA) inhibit growth hormone (GH) secretion and proliferation of GH-secreting pituitary adenomas (GHomas) through binding to SSTR2 and D2R receptors. Chimeric SST-DA compounds (Dopastatins) display increased potency in inhibiting GH secretion, as compared with individual SST or DA analogs (alone or combined).OBJECTIVETo assess the efficacy of a second-generation dopastatin, TBR-065, in suppressing GH secretion from human GH- and GH/prolactin(PRL)-omas.DESIGNWe compared the ability of TBR-065 to inhibit GH secretion from primary cultures of human GH- or GH/PRLoma cells to that of the first generation dopastatin, TBR-760 (formerly BIM-23A760), octreotide (OCT) and cabergoline (CAB), the later either alone or combined. We investigated whether there was any impact of BIM-133, the metabolite of TBR-065, on the ability of TBR-065 to inhibit GH in these cultures.METHODS17 GH- and GH/PRLomas were included in this study. Inhibition of GH secretion by TBR-065, TBR-760, OCT and CAB (0.1 pM to 0.1 µM) was assessed over a period of 8 h.RESULTSAll tumors expressed SSTR2 and D2R mRNAs. GH suppression was higher with TBR-065 as compared with TBR-760 (E_max = 57 ± 5.6% vs. 41.1 ± 12.5%, respectively, p < 0.001) or with OCT + CAB (E_max = 56.8 ± 7.2% vs. 44.4 ± 9.4%, p < 0.001). BIM-133 did not have any impact on the activity of TBR-065.CONCLUSIONTBR-065 has significantly improved efficacy in suppressing GH secretion as compared to current available therapies and may represent a new promising option for the treatment of acromegaly.

2020-08-01·Endocrinology2区 · 医学

TBR-760, a Dopamine-Somatostatin Compound, Arrests Growth of Aggressive Nonfunctioning Pituitary Adenomas in Mice

2区 · 医学

Article

作者: Halem, Heather A ; Johnson, G Allan ; Thiagalingam, Arunthi ; Culler, Michael D ; Hochgeschwender, Ute ; Nelson, Richard ; Rih, Jeong Keun

AbstractTBR-760 (formerly BIM-23A760) is a chimeric dopamine (DA)-somatostatin (SST) compound with potent agonist activity at both DA type 2 (D2R) and SST type 2 (SSTR2) receptors. Studies have shown that chimeric DA-SST compounds are more efficacious than individual DA and/or SST analogues, either alone or combined, in inhibiting secretion from primary cultures of human somatotroph and lactotroph tumor cells. Nonfunctioning pituitary adenomas (NFPAs) express both D2R and SSTR2 and, consequently, may respond to TBR-760. We used a mouse model with the pro-opiomelanocortin (POMC) gene knocked out that spontaneously develops aggressive NFPAs. Genomic microarray and DA and SST receptor messenger RNA expression analysis indicate that POMC KO mouse tumors and human NFPAs have similar expression profiles, despite arising from different cell lineages, establishing POMC KO mice as a model for study of NFPAs. Treatment with TBR-760 for 8 weeks resulted in nearly complete inhibition of established tumor growth, whereas tumors from vehicle-treated mice increased in size by 890 ± 0.7%. Comparing TBR-760 with its individual DA and SST components, TBR-760 arrested tumor growth. Treatment with equimolar or 10×-higher doses of the individual SST or DA agonists, either alone or in combination, had no significant effect. One exception was the lower dose of DA agonist that induced modest suppression of tumor growth. Only the chimeric compound TBR-760 arrested tumor growth in this mouse model of NFPA. Further, significant tumor shrinkage was observed in 20% of the mice treated with TBR-760. These results support the development of TBR-760 as a therapy for patients with NFPA.

2020-01-01·Neuroendocrinology2区 · 医学

A New Generation Somatostatin-Dopamine Analogue Exerts Potent Antitumoral Actions on Pituitary Neuroendocrine Tumor Cells

2区 · 医学

Article

作者: Vázquez-Borrego, Mari C ; L-López, Fernando ; Landsman, Tanya ; Venegas-Moreno, Eva ; Luque, Raúl M ; Herrera-Martínez, Aura D ; Culler, Michael D ; Blanco-Acevedo, Cristóbal ; Fuentes-Fayos, Antonio C ; Soto-Moreno, Alfonso ; Solivera, Juan ; Castaño, Justo P ; Gálvez-Moreno, María A ; Gahete, Manuel D

Background: Pituitary neuroendocrine tumors (PitNETs) represent approximately 15% of all intracranial tumors and usually are associated with severe comorbidities. Unfortunately, a relevant number of patients do not respond to currently available pharmacological treatments, that is, somatostatin analogs (SSAs) or dopamine-agonists (DA). Thus, novel, chimeric somatostatin/dopamine compounds (dopastatins) that could improve medical treatment of PitNETs have been designed. Objective: This study aims to determine the direct therapeutic effects of a new-generation dopastatin, BIM-065, on primary cell cultures from different PitNETs subtypes. Methods: Thirty-one PitNET-derived cell cultures (9 corticotropinomas, 9 somatotropinomas, 11 nonfunctioning pituitary adenomas [NFPAs], and 2 prolactinomas), were treated with BIM-065, and key functional endpoints were assessed (cell viability, apoptosis, hormone secretion, expression levels of key genes, free cytosolic [Ca2+]i dynamics, etc.). AtT-20 cell line was used to evaluate signaling pathways in response to BIM-065. Results: This chimeric compound decreased cell viability in all corticotropinomas and somatotropinomas tested, but not in NFPAs. BIM-065 reduced ACTH, GH, chromogranin-A and PRL secretion, and increased apoptosis in corticotropinomas, somatotropinomas, and NFPAs. These effects were possibly mediated through modulation of pivotal signaling cascades like [Ca2+]i kinetic and Akt- or ERK1/2-phosphorylation. Conclusions: Our results unveil a robust antitumoral effect in vitro of the novel chimeric compound BIM-065 on the main PitNET subtypes, inform on the mechanisms involved, and suggest that BIM-065 could be an efficacious therapeutic option to be considered in the treatment of PitNETs.

100 项与 Dopastatin 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16144

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
恶性类癌综合征	临床2期	荷兰	Ipsen SA	2010-02-01
恶性类癌综合征	临床2期	比利时	Ipsen SA	2010-02-01
恶性类癌综合征	临床2期	奥地利	Ipsen SA	2010-02-01
恶性类癌综合征	临床2期	俄罗斯	Ipsen SA	2010-02-01
恶性类癌综合征	临床2期	西班牙	Ipsen SA	2010-02-01
恶性类癌综合征	临床2期	以色列	Ipsen SA	2010-02-01
肢端肥大症	临床2期	欧盟	Ipsen SA	-
恶性类癌综合征	临床前	爱尔兰	Ipsen SA	2010-02-01
恶性类癌综合征	药物发现	捷克	Ipsen SA	2010-02-01
恶性类癌综合征	药物发现	拉脱维亚	Ipsen SA	2010-02-01

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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


NCT01018953 (CAMPANULA, CTgov)	临床2期	恶性类癌综合征	8	BIM 23A760	積積膚窪構廠鹽廠襯簾(遞遞鹽糧醖積鹽衊選鏇) = 衊製憲齋衊膚願鹽餘鏇窪構夢膚獵網築壓餘夢 (鏇製觸醖鏇遞齋繭鹽製, 獵鑰蓋製蓋築顧醖糧壓 ~ 遞襯餘網壓夢範憲積構) 更多	-	2015-09-07