CAP-232(CAP-232) - 药物靶点：PKM2 x SSTR1_专利_临床

概要

基本信息

药物类型

合成多肽

别名

靶点

PKM2 x SSTR1

作用机制

PKM2抑制剂(丙酮酸激酶M1/M2型同功酶抑制剂)、SSTR1激动剂(生长抑素受体1激动剂)

治疗领域

肿瘤皮肤和肌肉骨骼疾病泌尿生殖系统疾病+ [2]

在研适应症-

非在研适应症

肾肿瘤转移性黑色素瘤转移性肾细胞癌+ [2]

原研机构

Biostatin Research & Development Ltd.

在研机构-

非在研机构

Thallion Pharmaceuticals, Inc.

BELLUS Health, Inc.Biosignal Ltd.

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C45H58N10O9S2

InChIKeySNAJPQVDGYDQSW-DYCFWDQMSA-N

CAS号147159-51-1

序列信息

Sequence Code 524989767

关联

3

项与 CAP-232 相关的临床试验

NCT00735332 / Terminated临床2期

A Phase IIa Study of TLN-232 as Second-line Therapy for Patients With Metastatic Melanoma

The objective of this study is to assess the efficacy and safety of TLN-232 used to treat patients with metastatic melanoma that recur/progress after receiving first line systemic therapy.

开始日期2008-08-01

申办/合作机构

Thallion Pharmaceuticals, Inc.

NCT00422786 / Completed临床2期

A Multi-Centre, Open Label, Phase II Study of the Safety, Efficacy and Pharmacokinetic (PK) Profile of CAP-232 Administered Through Continuous Intravenous Infusion in Patients With Metastatic Kidney Cancer

The purpose of this study was to evaluate the safety and efficacy of CAP-232 in the treatment of patients with previously treated (refractory) renal cell carcinoma

开始日期2007-03-01

申办/合作机构

Thallion Pharmaceuticals, Inc.

EUCTR2006-004857-86-FR / Unknown statusN/A

A multi-centre, open-label, phase II study of the safety, efficacy and pharmacokinetic (PK) profile of CAP-232 administered through continuous intravenous infusion in patients with metastatic kidney cancer

开始日期2007-01-19

申办/合作机构

Caprion Pharmaceuticals, Inc.

100 项与 CAP-232 相关的临床结果

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100 项与 CAP-232 相关的转化医学

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100 项与 CAP-232 相关的专利（医药）

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40

项与 CAP-232 相关的文献（医药）

2023-05-24·Journal of Biomolecular Structure and Dynamics

Exploring species-specific inhibitors with multiple target sites on S. aureus pyruvate kinase using a computational workflow

Article

作者: Ates, Beril ; Kurkcuoglu, Ozge ; Yuce, Merve ; Sarica, Zehra

Experimental evidence indicated that bacterial pyruvate kinase of glycolysis can be evaluated as an alternative target to eliminate infections, while antibiotic resistance poses a global threat. Here, we use a computational workflow to reveal and investigate the potential allosteric sites of methicillin-resistant S. aureus PK, which can help in designing species-specific drugs to inhibit activity of this organism. Residue interaction networks point to a known allosteric site at the small C-C interface, a potential allosteric site near the small interface (site #1), and a second potential allosteric site at the large interface (site #2). 2 µs-long molecular dynamics (MD) simulations with AMBER16 generate different conformations of one narrow target site. Known and potential allosteric sites on the selected conformers are investigated using ensemble docking with AutoDock Vina and a library of 2447 FDA-approved drugs. We determine 18 hits, comprising ergot-alkaloids, anti-cancer-agents, antivirals, analgesics, cardiac glycosides, all with a high docking z-score for three sites. 5 selected compounds with high, average and low z-scores are subjected to 50 ns-long MD simulations for MM-GBSA calculations. ΔG_bind values up to -49.3 kcal/mol at the C-C interface, up to -32.7 kcal/mol at site #1, and up to -53.3 kcal/mol at site #2 support the docking calculations. We investigate mitapivat and TT-232 as reference compounds under clinical trial, targeting human PK isomers. We suggest 18 FDA-approved hits from the docking calculations and TT-232 as potential inhibitors with multiple target sites on S. aureus PK. This study also proposes pharmacophores models for de novo drug design.Communicated by Ramaswamy H. Sarma.

2023-03-01·Biochemical Pharmacology

The heptapeptide somatostatin analogue TT-232 exerts analgesic and anti-inflammatory actions via SST4 receptor activation: In silico, in vitro and in vivo evidence in mice

Article

作者: Hudhud, Lina ; Hetényi, Csaba ; Horváth, Ádám ; Pintér, Erika ; Borbély, Éva ; Szőke, Éva ; Börzsei, Rita ; Helyes, Zsuzsanna ; Kántás, Boglárka

Since the conventional and adjuvant analgesics have limited effectiveness frequently accompanied by serious side effects, development of novel, potent pain killers for chronic neuropathic and inflammatory pain conditions is a big challenge. Somatostatin (SS) regulates endocrine, vascular, immune and neuronal functions, cell proliferation through 5 G_i protein-coupled receptors (SST₁-SST₅). SS released from the capsaicin-sensitive peptidergic sensory nerves mediates anti-inflammatory and antinociceptive effects without endocrine actions via SST₄. The therapeutic use of the native SS is limited by its diverse biological actions and short plasma elimination half-life. Therefore, SST₄ selective SS analogues could be promising analgesic and anti-inflammatory drug candidates with new mode of action. TT-232 is a cyclic heptapeptide showing great affinity to SST₄ and SST₁. Here, we report the in silico SST₄ receptor binding mechanism, in vitro binding (competition assay) and cAMP- decreasing effect of TT-232 in SST₄-expressing CHO cells, as well as its analgesic and anti-inflammatory actions in chronic neuropathic pain and arthritis models using wildtype and SST₄-deficient mice. TT-232 binds to SST₄ with similar interaction energy (-11.03 kcal/mol) to the superagonist J-2156, displaces somatostatin from SST₄ binding (10 nM to 30 µM) and inhibits forskolin-stimulated cAMP accumulation (EC₅₀: 371.6 ± 58.03 nmol; E_max: 78.63 ± 2.636 %). Its i.p. injection (100, 200 µg/kg) results in significant, 35.7 % and 50.4 %, analgesic effects upon single administration in chronic neuropathic pain and repeated injection in arthritis models in wildtype, but not in SST₄-deficient mice. These results provide evidence that the analgesic effect of TT-232 is mediated by SST₄ activation, which might open novel drug developmental potentials. Chemical compounds Chemical compounds studied in this article TT-232 (PubChem CID: 74053735).

2022-09-01·Basic & Clinical Pharmacology & Toxicology

Somatostatin receptor ligands suppressed proliferation and lipogenesis in 3T3‐L1 preadipocytes

Article

作者: Tang, Yan ; Lv, Xiaorui ; Duan, Lian ; Zhu, Huijuan ; Zhao, Zhe ; Chen, Xiaoguang ; Gong, Fengying ; Wu, Haijie

AbstractSomatostatin and its analogues, known as somatostatin receptor ligands (SRLs), have been reported to attenuate weight gain in some clinical settings. However, their direct effects on preadipocytes are barely investigated. Therefore, this study aimed to evaluate the influence of SRLs on preadipocytes and to further explore the potential mechanisms. Cell Counting Kit‐8 assay, Oil Red O staining, triglyceride contents measurements, quantitative polymerase chain reaction (qPCR) and western blot were used to investigate the effects of SRLs on preadipocytes. We found that three SRLs (octreotide, TT232 and pasireotide) inhibited cell viability after 8–48 h but not 4 h. Further western blot results showed that they significantly suppressed activation of PI3K/Akt pathway. Besides, lipid accumulation was also significantly inhibited by these SRLs. Moreover, mRNA levels of some critical adipogenic markers, including Pparg, Cebpa, Fasn, Fabp4, Acaca and Lpl, were downregulated by the treatments of all these SRLs. Consistently, the protein expression of peroxisome proliferator‐activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα) and fatty acid synthase (FAS) was also suppressed by SRLs. SRLs inhibit the proliferation and lipogenesis in preadipocytes. Their inhibitory effects on cell proliferation may be mediated by the downregulated PI3K/Akt pathway, and the suppressive actions on lipogenesis may be related to the decreased PPARγ and C/EBPα expression.

100 项与 CAP-232 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12088

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
胰腺癌	临床2期	加拿大	Thallion Pharmaceuticals, Inc.	2009-09-02
转移性黑色素瘤	临床2期	美国	Thallion Pharmaceuticals, Inc.	2008-08-01
转移性黑色素瘤	临床2期	加拿大	Thallion Pharmaceuticals, Inc.	2008-08-01
转移性肾细胞癌	临床2期	法国	Thallion Pharmaceuticals, Inc.	2007-03-01
肿瘤	临床2期	美国	Biosignal Ltd.	2002-10-20
肾肿瘤	临床2期	法国	BELLUS Health, Inc.	-