Delving into the Latest Updates on Dopastatin with Synapse

Overview

Basic Info

Drug Type

Synthetic peptide

Synonyms

Target

D2 receptor x SSTR2 x SSTR5

Action

agonists

Mechanism

D2 receptor agonists(Dopamine D2 receptor agonists), SSTR2 agonists(Somatostatin receptor 2 agonists), SSTR5 agonists(Somatostatin receptor 5 agonists)

Therapeutic Areas

NeoplasmsNervous System DiseasesEndocrinology and Metabolic Disease+ [2]

Active Indication-

Inactive Indication

AcromegalyAdenocarcinomaMalignant Carcinoid Syndrome+ [2]

Originator Organization

Ipsen SA

Active Organization-

Inactive Organization

Ipsen SA

Tiburio Therapeutics, Inc.

License Organization

Ipsen SA

Tiburio Therapeutics, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC86H116N16O12S4

InChIKeyWLBJBODHTIKYSL-JFPOTJHNSA-N

CAS Registry868562-36-1

Sequence Code 525125508

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.

01 Aug 2020·EndocrinologyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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.

01 Jan 2020·NeuroendocrinologyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Vázquez-Borrego, Mari C ; L-López, Fernando ; Landsman, Tanya ; Luque, Raúl M ; Venegas-Moreno, Eva ; 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 Deals associated with Dopastatin

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16144

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acromegaly	Phase 2	Belgium	Ipsen SA	01 Oct 2009
Acromegaly	Phase 2	France	Ipsen SA	01 Oct 2009
Acromegaly	Phase 2	Poland	Ipsen SA	01 Oct 2009
Acromegaly	Phase 2	Mexico	Ipsen SA	01 Oct 2009
Acromegaly	Phase 2	United States	Ipsen SA	01 Oct 2009
Acromegaly	Phase 2	Sweden	Ipsen SA	01 Oct 2009
Acromegaly	Phase 2	Romania	Ipsen SA	01 Oct 2009
Acromegaly	Phase 2	Latvia	Ipsen SA	01 Oct 2009
Acromegaly	Phase 2	Lithuania	Ipsen SA	01 Oct 2009
Acromegaly	Phase 2	Netherlands	Ipsen SA	01 Oct 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01018953 (CAMPANULA, CTgov)	Phase 2	Malignant Carcinoid Syndrome	8	BIM 23A760	(lzfsvhpyse) = vtajvpukir mqzwjtsday (ezrisczfce, znfxkgvmiq - uxcmlkvqik) View more	-	07 Sep 2015

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Biosimilar

Competitive landscape of biosimilars in different countries/locations. Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3.

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Competitive landscape of biosimilars in different countries/locations. Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3.

Regulation

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Dopastatin

Overview

Basic Info

Structure/Sequence

Related

External Link

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Biosimilar

Regulation