Delving into the Latest Updates on CAP-232 with Synapse

Overview

Basic Info

Drug Type

Synthetic peptide

Synonyms

Target

PKM2 x SSTR1

Mechanism

PKM2 inhibitors(Pyruvate kinase isozymes M1/M2 inhibitors), SSTR1 agonists(Somatostatin receptor 1 agonists)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesUrogenital Diseases+ [2]

Active Indication-

Inactive Indication

Kidney NeoplasmsMetastatic melanomaMetastatic Renal Cell Carcinoma+ [2]

Originator Organization

Biostatin Research & Development Ltd.

Active Organization-

Inactive Organization

Thallion Pharmaceuticals, Inc.

BELLUS Health, Inc.Biosignal Ltd.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC45H58N10O9S2

InChIKeySNAJPQVDGYDQSW-DYCFWDQMSA-N

CAS Registry147159-51-1

Gene Sequence

Sequence Code 524989767

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.

01 Mar 2023·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

Author: 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).

01 Sep 2022·Basic & Clinical Pharmacology & Toxicology

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

Article

Author: Tang, Yan ; Lv, Xiaorui ; Duan, Lian ; Zhao, Zhe ; Zhu, Huijuan ; 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 Deals associated with CAP-232

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12088

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pancreatic Cancer	Phase 2	CA	Thallion Pharmaceuticals, Inc.	02 Sep 2009
Metastatic melanoma	Phase 2	US	Thallion Pharmaceuticals, Inc.	01 Aug 2008
Metastatic melanoma	Phase 2	CA	Thallion Pharmaceuticals, Inc.	01 Aug 2008
Metastatic Renal Cell Carcinoma	Phase 2	FR	Thallion Pharmaceuticals, Inc.	01 Mar 2007
Neoplasms	Phase 2	US	Biosignal Ltd.	20 Oct 2002
Kidney Neoplasms	Phase 2	FR	BELLUS Health, Inc.	-