NCB-0846 / National Cancer Center, Carna Biosci - LARVOL DELTA

TRAF2 and NCK interacting kinase: a novel regulator of integrin αIIbβ3 signaling in platelets. (PubMed, Res Pract Thromb Haemost) - "The importance of platelet TNIK was explored using 2 structurally distinct TNIK inhibitors (KY-05009 and NCB-0846) in aggregometry, assays of granule secretion, calcium mobilization and thrombus formation, and using confocal microscopy and co-immunoprecipitation...For the first time, we show that platelet TNIK is able to associate with key cytoskeletal regulators, linking its signaling to integrin αIIbβ3 function. Future studies will focus on exploring a potential role of TNIK in the regulation of thrombosis and hemostasis in vivo to assess TNIK's potential as a novel antithrombotic target."

Journal • Cardiovascular • Hematological Disorders • Thrombosis • GSN

Identification of a TNIK-CDK9 axis as a targetable strategy for platinum-resistant ovarian cancer. (PubMed, Mol Cancer Ther) - "This identified TNIK, which is modulated by NCB-0846, as a novel target for platinum-resistant HGSC...Our findings identified the TNIK-CDK9 axis as druggable targets mediating platinum resistance and cell viability in HGSC. With AI at the forefront of drug discovery, this work highlights how to ensure that AI findings are biologically relevant by combining compound screens with physiologically relevant models thus supporting the identification and validation of potential drug targets."

Journal • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CDK9 • TNIK

TNIK Inhibition Sensitizes TNIK-Overexpressing Lung Squamous Cell Carcinoma to Radiotherapy. (PubMed, Mol Cancer Ther) - "The combination of NCB-0846 with cisplatin or etoposide was at best additive. In a subcutaneous xenograft in vivo model, pretreatment with NCB-0846 significantly enhanced the efficacy of IR and caused elevated necrosis in TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a promising strategy to increase the efficacy of radiotherapy in patients with LSCC with high TNIK expression."

IO biomarker • Journal • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma • TNIK

Therapeutic targeting of TNIK in papillary thyroid carcinoma: a novel approach for tumor growth suppression. (PubMed, Med Oncol) - "In summary, we proposed a novel regulatory mechanism in which TNIK-mediated cytoskeleton remodeling and cell migration to regulate tumor progression in PTC. TNIK is a therapeutic target in PTC and NCB-0846 would act as a novel targeted drug for PTC therapy."

Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • TNIK

TNIK inhibition sensitizes TNIK-overexpressing lung squamous cell carcinoma to radiotherapy. (PubMed, Mol Cancer Ther) - "The combination of NCB-0846 with cisplatin or etoposide was at best additive. In a subcutaneous xenograft in vivo model, pretreatment with NCB-0846 significantly enhanced the efficacy of IR and caused elevated necrosis in TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a promising strategy to increase the efficacy of radiotherapy in LSCC patients with high TNIK expression."

IO biomarker • Journal • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma • TNIK

The impact of targeting TRAF2 and NCK-interacting protein kinase on anti-tumor effect and tumor immune environment in cMYC-high small cell lung cancer (AACR 2024) - "Here, we hypothesize that targeting TNIK will show an anti-tumor effect based on specific biomarkers and also modify the tumor immune environment in SCLC. We evaluated susceptibility to a small molecule TNIK inhibitor, NCB-0846, in 29 human-derived SCLC cell lines using 96-hour proliferation assays... These findings show that TNIK inhibition is more effective in cMYC-high SCLC, acting through downregulating cMYC levels. TNIK inhibition also decreases the production of CCL2, an immunosuppressive chemokine implicated in resistance to anti-PD-L1 immunotherapy. Together, these findings highlight the promising potential of TNIK inhibitors in cMYC-high SCLC."

IO biomarker • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CCL2 • CTNNB1 • MYC • NKX2-1 • TCF4 • TNIK • TTF1

TNIK induced chemoradiation resistance in small cell lung cancer (AACR 2024) - "In vivo, pharmacological inhibition of TNIK with the inhibitor NCB-0846, enhances the CRT sensitivity of NCI-H446 cell line-derived xenografts (CDX) in NOD SCID immunodeficient mice. Furthermore, pharmacological inhibition of TNIK in vivo demonstrated sensitivity to CRT in LX33 PDX. In conclusion, our results indicate that TNIK plays a role in conferring resistance to CRT in vitro in SCLC cell lines and in vivo in SCLC CDX and PDX models and therefore, can be a potential therapeutic target in limited stage SCLC."

Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1. (PubMed, Genes Dis) - "In this study, we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpine-induced rat model of epilepsy by western blotting, immunofluorescence, and immunohistochemistry. A pentylenetetrazole (PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of epilepsy...In addition, the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ kindling. Our results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target."

Journal • CNS Disorders • Epilepsy • Mental Retardation • Psychiatry • GRIA1 • TNIK

TNIK inhibition as a novel therapeutic in cMyc high/TTF1 low SCLC (AACR 2023) - "These findings indicate that TNIK inhibitors may be a new personalized molecular-targeted therapy in cMyc-high/TTF-1-low SCLC."

Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • ASCL1 • CTNNB1 • MYC • NEUROD1 • NEUROD1 • NKX2-1 • POU2F3 • TCF4 • TNIK

Investigating TNIK as a radiosensitizing target in lung squamous cell carcinoma (AACR 2023) - "We observed that pretreatment with NCB-0846 significantly potentiated the efficacy of IR in eradicating TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a viable strategy to enhance the efficacy of radiotherapy in LSCC tumors with high TNIK expression."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • TNIK

Traf2 and NCK Interacting Kinase Is a Critical Regulator of Procollagen I Trafficking and Hepatic Fibrogenesis in Mice. (PubMed, Hepatol Commun) - "Mice receiving NCB-0846 displayed reduced CCl -induced fibrogenesis compared to CCl alone, although α-smooth muscle actin levels were unaltered. Our siRNA screen effectively identified TNIK as a key kinase involved in procollagen I trafficking in vitro and hepatic fibrogenesis in vivo."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Liver Failure • Oncology • TNFA

CRISPR screens identify a novel combination treatment targeting BCL-X and WNT signaling for KRAS/BRAF-mutated colorectal cancers. (PubMed, Oncogene) - "In addition, the combination of ABT-263 and NCB-0846 exhibited synergistic effects in in vivo patient-derived xenograft (PDX) models with KRAS mutations. Our data provide a novel targeted combination treatment strategy for the CRC patient subgroup with KRAS or BRAF mutations."

IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • BRAF • KRAS • MCL1

Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846. (PubMed, Br J Cancer) - "NCB-0846 pharmacologically blocks the TGFβ/SMAD signalling and EMT induction of lung cancer cells by transcriptionally downregulating TGFBRI expression, representing a potentially promising approach for prevention of metastasis in lung cancer patients."

Journal • Immune Modulation • Inflammation • Lung Cancer • Oncology • Solid Tumor

[VIRTUAL] TNIK IS A NOVEL PROCOLLAGEN I TRAFFICKING PROTEIN THAT CAN BE TARGETED IN VIVO TO LIMIT FIBROSIS (AASLD 2020) - "A novel in vitro IF screen successfully identified TNIK as a critical player in PC-1 trafficking and fibrogenesis in vivo."

Preclinical • Fibrosis • Hepatology • Immunology • Liver Failure • CCL4 • FN1 • PDGFRB

Feasibility of Targeting Traf2-and-Nck-Interacting Kinase in Synovial Sarcoma. (PubMed, Cancers (Basel)) - "It has become evident that activation of Wnt signaling is causatively involved in the pathogenesis of synovial sarcoma, but no molecular therapeutics targeting the pathway have been approved. This study revealed for the first time the therapeutic potential of TNIK inhibition in synovial sarcoma."

Journal • Oncology • Sarcoma • Solid Tumor

Characterization of the ERG-regulated Kinome in Prostate Cancer Identifies TNIK as a Potential Therapeutic Target. (PubMed, Neoplasia) - "Furthermore, reduction of TNIK expression and activity by silencing TNIK expression or using the TNIK inhibitor NCB-0846 reduced cell viability, colony formation and anchorage independent growth. Therefore, TNIK represents a novel and actionable therapeutic target for ERG-positive prostate cancers that could be exploited to develop new treatments for these patients."

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