INCB3344 / Incyte - LARVOL DELTA

Beyond Impaired GABAergic Signaling: Inflammation and Metabolic Dysfunction in Genetic Epilepsy Induced by GABRG2 Mutation. (PubMed, Mol Neurobiol) - "In addition to impairing receptor trafficking, the γ2(I107T) mutation may induce ER stress, and disrupt inflammatory and metabolic pathways, thereby leading to an imbalance of excitatory/inhibitory neurotransmission and potentially contributing to the pathogenesis of genetic epilepsy. Pharmacological intervention with dexamethasone and INCB3344, a C-C chemokine receptor type 2 antagonist, ameliorated seizure-like behavior in Tg(hGABRG2I107T) zebrafish, further supporting the causal role of neuroinflammation in epileptogenesis in genetic epilepsy."

Journal • CNS Disorders • Epilepsy • Inflammation • Metabolic Disorders • FOS • TGFB1

Circulating monocyte adhesion repairs endothelium-denuded injury through downstream of kinase 3-mediated endothelialization. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "However, this process was inhibited by the CCR2B inhibitor INCB3344...Bindarit, a selective MCP1 inhibitor, suppressed endothelialization following CCAED surgery in WT mice but not in DOK3-/- mice. In conclusion, endothelialization mediated by circulating monocytes repairs endothelium-denuded injury to compensate for endothelial functions through MCP1/DOK3/CCR2B/Ca2+ signaling. Our findings indicate that circulating monocyte adhesion is an important endothelial wound healing mechanism."

Journal • Cardiovascular • Hematological Disorders • Thrombosis • CCL2 • CCR2

CC chemokine receptor 2 is allosterically modulated by sodium ions and amiloride derivatives through a distinct sodium ion binding site. (PubMed, Biochem Pharmacol) - "Only two mutants, G123A3.35 and G127K3.39, were able to be bound by [3H]INCB3344 and [3H]CCR2-RA-[R]. Moreover, the tested mutations appeared to have no effect on modulation observed by HMA or a minor effect on sodium chloride modulation on the tested radioligands. All in all, these results invite further exploration of the CCR2 sodium ion binding site in (cancer) biology, and potentially as a third druggable binding site."

Journal • Immune Modulation • Immunology • Oncology • Solid Tumor • CCL2 • CCR2

Transcription factor EHF drives cholangiocarcinoma development through transcriptional activation of glioma-associated oncogene homolog 1 and chemokine CCL2. (PubMed, MedComm (2020)) - "Furthermore, the combination of the GLI1 inhibitor, GANT58, and CCR2 inhibitor, INCB3344, substantially reduced the occurrence of EHF-mediated CCA. In summary, our findings suggest that EHF is a potential prognostic biomarker for patients with CCA, while also advocating the therapeutic approach of combined targeting of GLI1 and CCL2/CCR2-TAMs to inhibit EHF-driven CCA development."

Journal • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • CNS Tumor • Gastrointestinal Cancer • Glioma • Oncology • Solid Tumor • CCL2 • CCR2 • GLI1

CC Chemokine Family Members' Modulation as a Novel Approach for Treating Central Nervous System and Peripheral Nervous System Injury-A Review of Clinical and Experimental Findings. (PubMed, Int J Mol Sci) - "Over the past several years, the results of studies in which available pharmacological tools were used indicated that blocking individual receptors, e.g., CCR1 (J113863 and BX513), CCR2 (RS504393, CCX872, INCB3344, and AZ889), CCR3 (SB328437), CCR4 (C021 and AZD-2098), and CCR5 (maraviroc, AZD-5672, and TAK-220), has beneficial effects after damage to both the CNS and PNS...In addition, both single (J113863, RS504393, SB328437, C021, and maraviroc) and dual (cenicriviroc) chemokine receptor antagonists enhanced the analgesic effect of opioid drugs. This review will display the evidence that a multidirectional strategy based on the modulation of neuronal-glial-immune interactions can significantly improve the health of patients after CNS and PNS damage by changing the activity of chemokines belonging to the CC family. Moreover, in the case of pain, the combined administration of such antagonists with opioid drugs could reduce therapeutic doses and minimize the risk of..."

Journal • Review • Immunology • Pain • CCL11 • CCL18 • CCL19 • CCL2 • CCL20 • CCL21 • CCL22 • CCL23 • CCL3 • CCL8 • CCR2 • CCR3 • CCR4

CCR2 antagonist attenuates calcium oxalate-induced kidney oxidative stress and inflammation by regulating macrophage activation. (PubMed, Exp Anim) - "Eight-week-old male C57BL/6J mice were intraperitoneally injected with glyoxylate (GOX) daily to establish a KS model, and along with CCR2 antagonist (INCB3344) treatment on days 2, 4, and 6...CCR2 antagonist inhibited CaOx-induced THP-1 cell M1 polarization by decreasing the TNF-α, IL6 and iNOS levels, and further alleviated CaOx-induced oxidative stress damage, inflammatory response and apoptosis of HK-2 cells. The study suggests that CCR2 antagonist may be resistant to CaOx crystals-induced oxidative stress and inflammation by inhibiting macrophage M1 polarization."

IO biomarker • Journal • Inflammation • Nephrology • Renal Calculi • Renal Disease • BCL2 • CASP3 • CAT • CCR2 • IL1B • IL6 • NFE2L2 • TNFA

Peripheral CCL2 induces inflammatory pain via regulation of I currents in small diameter DRG neurons. (PubMed, Front Mol Neurosci) - "Further studies revealed that inflammatory pain caused by CFA or incubation of DRG with CCL2 mainly affected I currents in small-diameter DRG neurons, which were blocked by co-incubation CCR2 antagonist INCB3344 or adenylate cyclase inhibitor SQ22536. Immunohistochemical staining showed that both intraplantar injection of CFA as well as DRG injection of CCL2 resulted in significant upregulation of CCR2/HCN2 expression. In conclusion, we suggest in the inflammatory pain state, CCL2 can act on small-diameter DRG neurons, leading to upregulation of HCN2 expression and consequently I, which in turn leads to neuronal hyperexcitability."

Journal • Pain • CCL2 • CCR2

Impact of cancer-associated mutations in CC chemokine receptor 2 on receptor function and antagonism. (PubMed, Biochem Pharmacol) - "Furthermore, INCB3344 and LUF7482 were chosen as representative orthosteric and allosteric antagonists, respectively. No change in potency was observed in a functional assay, but mutations located at F116 impacted orthosteric antagonist binding significantly, while allosteric antagonist binding was abolished for L134Q and D137N mutants. As CC chemokine receptor 2 is an attractive drug target in cancer, the negative effect of these mutations on receptor functionality and drugability should be considered in the drug discovery process."

Journal • Oncology • CCL2 • CCR2

Effects of a CCR2 antagonist on macrophages and Toll-like receptor 9 expression in a mouse model of diabetic nephropathy. (PubMed, Am J Physiol Renal Physiol) - "Both increased activation of BM-Mφs via TLR9 and TNF-α production and increased ROS production by Res-Mφs were involved in DN progression. Thus, inactivating macrophages and their TLR9 expressions by INCB3344 is a potential therapeutic strategy for diabetic nephropathy."

IO biomarker • Journal • Preclinical • Diabetic Nephropathy • Immunology • Inflammation • Kidney Cancer • Metabolic Disorders • Nephrology • Oncology • Renal Cell Carcinoma • Renal Disease • ITGAM • TLR9 • TNFA

Mechanistic insights into the role of the chemokine CCL2/CCR2 axis in dorsal root ganglia to peripheral inflammation and pain hypersensitivity. (PubMed, J Neuroinflammation) - "Our results provide significant mechanistic insights into the role of CCL2/CCR2 within the DRG in the development of peripheral inflammation, nociceptor sensitization, and pain hypersensitivity. We further unveil the therapeutic potential of targeting CCR2 for the treatment of painful inflammatory disorders."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Pain • Rheumatology • CCL2

Key role of CCR2-expressing macrophages in a mouse model of low back pain and radiculopathy. (PubMed, Brain Behav Immun) - "Three different experimental manipulations that reduced the CCR2 MØ influx also reduced pain behaviors: global CCR2 knockout; systemic injection of INCB3344 (specific CCR2 blocker); and intravenous injection of liposomal clodronate...Together these experiments suggest a key role for the CCR2/CCL2 system in establishing the pain state in this model of inflammatory low back pain and radiculopathy. Intravenous clodronate given after pain was established had the opposite effect on pain behaviors, suggesting the role of macrophages or their susceptibility to clodronate may change with time."

Journal • Preclinical • Back Pain • Immunology • Inflammation • Lumbar Back Pain • Musculoskeletal Pain • Pain

[VIRTUAL] CCR2:A potential target for lung injury resolution> (ERS 2020) - "We used rescue treatment of a specific CCR2 antagonist (INCB 3344) in WT-mice, injecting a dose of 100 mg/kg subcutaneously 2 days (daily for 3 days) after ALI models... Targeting CCR2 could represent a new target to accelerate resolution of lung injury. Funding DoD W81XWH-16-1-0510"

Acute Lung Injury • Immunology • Infectious Disease • Pneumonia • Respiratory Diseases • CCL2 • FOXP3

[VIRTUAL] Resolution of Lung Injury by Targeting CCR2 (ATS-I 2020) - "Targeting CCR2 could represent a new target to accelerate resolution of lung injury."

Acute Lung Injury • Immunology • Infectious Disease • Pneumonia • Respiratory Diseases • CCL2 • FOXP3

Acute immune response to spinal cord injury in the dorsal root ganglia as a predictor of pain development (Neuroscience 2017) - "We are conducting experiments to block myeloid cell infiltration using a CCR2 inhibitor (INCB3344) early (0-72h) post-SCI to prevent CCL2-mediated recruitment, and will assess the necessity of myeloid cell recruitment in the development of pain, as well as correlations between pain development and macrophage phenotype and inflammatory environment in the DRG. Studying the acute immune response after SCI in the DRG could reveal key mechanisms that initiate maladaptive processes that lead to nociceptor dysfunction and prolonged pain."

CNS Disorders • Pain

Resolution of Lung Injury by Targeting CCR2 (ATS 2020) - "Targeting CCR2 could represent a new target to accelerate resolution of lung injury."

CCL2 • FOXP3

Synergistic activation of Src, ERK and STAT pathways in PBMCs for Staphylococcal enterotoxin A induced production of cytokines and chemokines. (PubMed, Asian Pac J Allergy Immunol) - "Our work suggested that rSEA serves as a potent stimulant of PBMCs, and induces the release of cytokines and chemokines through Src, ERK and STAT pathways upon a relatively independent network. Our work also strongly supported that Src, ERK and STAT signaling inhibitors could be effective therapeutic agents against diseases like toxic shock syndrome or infection by microbes resistant to antibiotics."

IO Biomarker • Journal

CCL2-CCR2 Axis Potentiates NMDA Receptor Signaling to Aggravate Neuropathic Pain Induced by Brachial Plexus Avulsion. (PubMed, Neuroscience) - "A rat model of BPA on lower trunk (C8-T1) was established, and the sham- and BPA-operated animals were intrathecally injected with saline, CCR2 inhibitor INCB3344 and NMDAR antagonist DL-AP5 one week postoperatively, the behavioral performance of the treated animals and expressions of CCL2, CCR2, and NR2B in spinal cord sections of each group were examined...CCR2 and NMDAR inhibition efficiently alleviated mechanical allodynia caused by BPA either at early or late phase of neuropathic pain. Collectively, CCL2-CCR2 axis is associated with mechanical pain after BPA by elevating NMDAR signaling."

Journal • CCL2

CCL2/CCR2 Chemokine System in Embryonic Hypothalamus: Involvement in Sexually Dimorphic Stimulatory Effects of Prenatal Ethanol Exposure on Peptide-Expressing Neurons. (PubMed, Neuroscience) - "We also discovered that these effects are sexually dimorphic, consistently stronger in female embryos, and are blocked by maternal administration of a CCL2 antibody (1 and 5 µg/day, i.p., E10-E15) that neutralizes endogenous CCL2 and of a CCR2 antagonist INCB3344 (1 mg/day, i.p., E10-E15) that blocks CCL2's main receptor. These results, which in the embryo anatomically and functionally link the CCL2/CCR2 system to MCH neurons in the LH, suggest an important role for this neuroimmune system in mediating ethanol's sexually dimorphic, stimulatory effect on MCH neurons that may promote higher level of alcohol consumption described in females."

Journal

Hypothalamic CCL2/CCR2 chemokine system: Role in sexually dimorphic effects of maternal ethanol exposure on melanin-concentrating hormone and behavior in adolescent offspring. (PubMed, J Neurosci) - "We show that these neuronal and behavioral changes are similarly produced by maternal administration of CCL2 (4 or 8 μg/kg/d, E10-E15) and blocked by maternal administration of a CCR2 antagonist INCB3344 (1 mg/kg/d, E10-E15), and these effects of ethanol and CCL2 are sexually dimorphic, consistently stronger in females...We demonstrate in adolescent offspring that maternal administration of CCL2, like ethanol, stimulates these neurons and increases ethanol drinking and anxiety, and these effects of ethanol are blocked by maternal CCR2 antagonist and consistently stronger in females. This suggests that neuronal chemokine signaling linked to neuropeptides mediates effects of maternal ethanol exposure on adolescent offspring and contributes to higher levels of adolescent risk factors for alcohol use disorders in women."

Journal

Macrophage recruitment to the dorsal root ganglia modulates pain after spinal cord injury (Neuroscience 2019) - "...A subset of SCI rats received INCB3344, a CCR2 antagonist intravenously acutely after SCI (0-72hpi) to prevent macrophage recruitment to the DRG...While macrophages at 28dpi are pro-inflammatory and associated with pain, early macrophage recruitment may be anti-inflammatory and necessary to prevent pain. Future studies will examine the influence of macrophages on nociceptor electrophysiological dysfunction as a mechanism of DRG neuroimmune interactions contributing to SCI-induced neuropathic pain."

CCL2/CCR2 chemokine system in embryonic hypothalamus: Involvement in sexually dimorphic stimulatory effects of prenatal ethanol exposure on peptide-expressing neurons in embryo (Neuroscience 2019) - "...We also showed these effects in the embryo to be reversed by maternal administration of a CCL2 antibody (1 and 5 µg/day, i.p., E10-E15) that neutralizes endogenous CCL2 and the receptor antagonist INCB3344 (1 mg/day, i.p., E10-E15) that blocks CCR2. Notably, we discovered that these effects in the embryo are already sexually dimorphic, consistently stronger in female than male embryos, with endogenous CCL2 in males totally unresponsive to ethanol. These results, which link the CCL2/CCR2 system both anatomically and functionally to MCH neurons in the embryonic LH, suggest an important role for this neuroimmune system in mediating ethanol’s sexually dimorphic, stimulatory effect on MCH neurons that may contribute to the higher levels of adolescent risk factors for alcohol use disorders described in females."