Delving into the Latest Updates on Bindarit with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Bindarit (USAN/INN)

Target

CCL2

Mechanism

CCL2 inhibitors(C-C motif chemokine 2 inhibitors)

Therapeutic Areas

Immune System DiseasesCardiovascular DiseasesEndocrinology and Metabolic Disease+ [3]

Active Indication-

Inactive Indication

AlbuminuriaCoronary RestenosisDiabetic Nephropathies+ [3]

Originator Organization

Angelini Pharma, Inc.

Active Organization-

Inactive Organization

Angelini Pharma, Inc.

Aziende Chimiche Riunite Angelini Francesco - A.C.R.A.F. - SpA

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC19H20N2O3

InChIKeyMTHORRSSURHQPZ-UHFFFAOYSA-N

CAS Registry130641-38-2

Acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) represents a primary cause of treatment failure in non-small cell lung cancer (NSCLC) patients. Chemokine (C-C motif) ligand 2 (CCL2) is recently found to play a pivotal role in determining anti-cancer treatment response. However, the role and mechanism of CCL2 in the development of EGFR-TKIs resistance have not been fully elucidated. In the present study, we focus on the function of CCL2 in the development of acquired resistance to EGFR-TKIs in NSCLC cells. Our results show that CCL2 is aberrantly upregulated in EGFR-TKIs-resistant NSCLC cells and that CCL2 overexpression significantly diminishes sensitivity to EGFR-TKIs. Conversely, CCL2 suppression by CCL2 synthesis inhibitor, bindarit, or CCL2 knockdown can reverse this resistance. CCL2 upregulation can also lead to enhanced migration and increased expressions of epithelial-mesenchymal transition (EMT) markers in EGFR-TKI-resistant NSCLC cells, which could also be rescued by CCL2 knockdown or inhibition. Furthermore, our findings suggest that CCL2-dependent EGFR-TKIs resistance involves the AKT-EMT signaling pathway; inhibition of this pathway effectively attenuates CCL2-induced cell migration and EMT marker expression. In summary, CCL2 promotes the development of acquired EGFR-TKIs resistance and EMT while activating AKT signaling in NSCLC. These insights suggest a promising avenue for the development of CCL2-targeted therapies that prevent EGFR-TKIs resistance in NSCLC.

01 Oct 2024·Acta Pharmaceutica Sinica B

Choroid plexus CCL2‒CCR2 signaling orchestrates macrophage recruitment and cerebrospinal fluid hypersecretion in hydrocephalus

Article

Author: Liu, Wenke ; Wu, Ke ; Hui, Xuhui ; Li, Hanmei ; You, Shenglan ; Cheng, Jian ; Zhu, Lei ; Li, Yue ; Liu, Fei ; Gao, Huile ; Zhang, Huan ; Zhang, Yi ; Wang, Qiguang ; Qi, Xin

The choroid plexus (ChP) serves as the principal origin of cerebrospinal fluid (CSF). CSF hypersecretion due to ChP inflammation has emerged as an important pathogenesis of hydrocephalus recently. Nevertheless, the precise mechanisms of ChP inflammation and the ensuing CSF hypersecretion in hydrocephalus remain ill-defined. In the present study, we elucidate the critical role of macrophages in the pathogenesis of ChP inflammation. Specifically, we identify the chemokine CCL2, released by ChP epithelial cells, recruits CCR2⁺ monocytes to the ChP thereby inciting hydrocephalus pathogenesis. The accumulated ChP macrophages increase the inflammation in ChP epithelial cells through TNF-α/TNFR1/NF-κB signaling cascade, thereby leading to CSF hypersecretion. Strikingly, augmentation of ChP‒CCL2 using an adeno-associated viral approach (AAV) exacerbates macrophage recruitment, activation, and ventriculomegaly in rat PHH models. Systemic application of Bindarit, a specific CCL2 inhibitor, significantly inhibits ChP macrophage infiltration and activation and reduces CSF secretion rate. Furthermore, the administration of CCR2 antagonist (INCB 3284) reduces ChP macrophage accumulation and ventriculomegaly. This study not only unveils the ChP CCL2‒CCR2 signaling in the pathophysiology of hydrocephalus but also unveils Bindarit as a promising therapeutic choice for the management of posthemorrhagic hydrocephalus.

01 Apr 2024·Acta Pharmacologica Sinica

Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis

Article

Author: Li, Zhu-Xin ; Hu, Ze-Gang ; Chen, Xiao-Kang ; Zeng, Chun-Yu ; Wang, Wei Eric ; Wang, Feng ; Zhou, Lu ; He, Yan-Ji ; Lu, Bing-Jun ; Li, Liang-Peng ; Wang, Wei ; Xia, Xue-Wei

Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 μg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 μM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 μM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.

100 Deals associated with Bindarit

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External Link

KEGG	Wiki	ATC	Drug Bank
D03116	-	-	DB12739

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Coronary Restenosis	Phase 2	IT	Aziende Chimiche Riunite Angelini Francesco - A.C.R.A.F. - SpA	01 Jan 2009
Albuminuria	Phase 2	SI	Aziende Chimiche Riunite Angelini Francesco - A.C.R.A.F. - SpA	01 Mar 2007
Albuminuria	Phase 2	IT	Aziende Chimiche Riunite Angelini Francesco - A.C.R.A.F. - SpA	01 Mar 2007
Diabetic Nephropathies	Phase 2	SI	Aziende Chimiche Riunite Angelini Francesco - A.C.R.A.F. - SpA	01 Mar 2007
Diabetic Nephropathies	Phase 2	IT	Aziende Chimiche Riunite Angelini Francesco - A.C.R.A.F. - SpA	01 Mar 2007
Lupus Nephritis	Phase 2	IT	Angelini Pharma, Inc.	-
Pancreatitis	Phase 2	IT	Angelini Pharma, Inc.	-
Rheumatoid Arthritis	Phase 2	IT	Angelini Pharma, Inc.	-
Rheumatoid Arthritis	Phase 2	US	Angelini Pharma, Inc.	-
Rheumatoid Arthritis	Phase 2	GB	Angelini Pharma, Inc.	-