tanzisertib (CC 930) / BMS - LARVOL DELTA

Single-cell transcriptome sequencing to explore the infiltration and disappearance of NK cells in liver cancer. (ASCO 2024) - "The study also investigated the role of c-Jun N-terminal protein kinase (JNK) in NK cell function by applying the JNK inhibitor tanzisertib (CC-930) in vitro... The NK cells in HCC tumors are likely derived from the infiltration of NK cells in peripheral blood. Importantly, the inhibition of JNK function can significantly inhibit the apoptosis of NK cells and enhance the killing ability of NK cells against tumor cells in vivo."

Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • PRKDC

Identification of potential JNK3 inhibitors through virtual screening, molecular docking and molecular dynamics simulation as therapeutics for Alzheimer's disease. (PubMed, Mol Divers) - "The ∆GMM/PBSA_total score for the lead compounds ZINC220382956, ZINC147071339, ZINC207081127, ZINC205151456, ZINC1228819126, and CC-930 was calculated and found to be - 31.39, - 42.8, - 37.04, - 39.01, - 36.5, - 34.16 kcal/mol, respectively. Thus, it was concluded that the lead molecules identified in these studies have the potential to be explored as potent JNK3 inhibitors."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • Pain • MAPK8

Integrative multiomics analysis of poor risk AML rationalizes differential drug responses in cases with mature and primitive molecular landscapes (EACR 2023) - "Classification of AML cases into primitive (n=12) and mature (n=10) revealed that primitive cells were more sensitive to 22 compounds including azacitidine and navitoclax. In contrast, mature cells were preferentially sensitive to 17 compounds including the MLC1 inhibitor A-1210477, the TLR8 agonist motolimod, the ROS inducer auranofin and 4 IAPs inhibitors...Mature cells increased the phosphorylation of stress response proteins like ASK1, P38A, JNK1 at and ATF7 at regulatory sites, but were more resistant to the P38 and JNK inhibitors ralimetinib and tanzisertib, respectively.ConclusionThe higher activity of the stress response pathway in mature cells could be the reason for their higher sensitivity to compounds that either induce (Auranofin) or modulate (IAPs inhibitors) the stress response. Overall, our integrative analysis is a rich source of molecular information to rationalize specific drug sensitivities of poor risk AML cases with mature and primitive phenotypes...."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Aplastic Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • MAPK8 • TLR8

Inhibition of the MAPK/c-Jun-EGR1 Pathway Decreases Photoreceptor Cell Death in the rd1 Mouse Model for Inherited Retinal Degeneration. (PubMed, Int J Mol Sci) - "Photoreceptor cell death was assessed using the TUNEL assay following silencing/overexpression of EGR1 or administration of MAPK/c-Jun pathway inhibitors tanzisertib and PD98059. Our study revealed that inhibition of the MAPK/c-Jun pathway reduced the expression of EGR1 and PARP1 and prevented photoreceptor cell death. These results highlight the importance of EGR1 for photoreceptor cell death and identify a new avenue for therapeutic interventions in RP."

Journal • Preclinical • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • EGR1 • JUN • PARP1

Mice with established diabetes show increased susceptibility to renal ischaemia/reperfusion injury: protection by blockade of JNK or SYK signalling pathways. (PubMed, Am J Pathol) - "In conclusion, established diabetes in mice predisposes to renal IRI-induced acute kidney injury. Two distinct pro-inflammatory pathways, JNK and SYK, are identified as potential therapeutic targets for anticipated acute kidney injury in diabetic individuals."

Journal • Preclinical • Acute Kidney Injury • Diabetes • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • Reperfusion Injury • SYK

Discovery of the c-Jun N-Terminal Kinase Inhibitor CC-90001. (PubMed, J Med Chem) - P2 | "As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001, which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191)."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • MAPK8 • MAPK9

[VIRTUAL] Discovery of CC-90001: A potent c-Jun N-terminal kinase (JNK) inhibitor for the treatment of fibrotic diseases (ACS-Fall 2021) - "As a result of emergent biological data that suggested JNK1 is the isoform primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with increased JNK1 activity relative to the first-generation, strongly JNK2-biased inhibitor tanzisertib (CC-930). CC-90001 is currently being studied in Phase II clinical trials for the treatment of patients with idiopathic pulmonary fibrosis (IPF) and non-alcoholic steatohepatitis (NASH) with liver fibrosis. Preclinical SAR development and physicochemical property optimization providing for the identification and selection of CC-90001 will be presented along with preclinical efficacy and selected human clinical trial data."

Fibrosis • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Liver Cirrhosis • Non-alcoholic Steatohepatitis • Pulmonary Disease • Respiratory Diseases • MAPK8

c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury. (PubMed, Front Physiol) - "In the chronic model, CC-930 treatment inhibited JNK signaling but did not affect AA-induced renal function impairment, tubular cell damage including the DNA damage response and induction of senescence, or renal fibrosis; despite a reduction in the macrophage pro-inflammatory response. In conclusion, JNK signaling contributes to acute high dose AA-induced tubular cell damage, presumably via an oxidative stress-dependent mechanism, but is not involved in tubular atrophy and senescence that promote chronic kidney disease caused by ongoing DNA damage in chronic low dose AA exposure."

Journal • Acute Kidney Injury • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • JUN

JNK1 signaling in the proximal tubule causes cell death and acute renal failure in rat and mouse models of renal ischaemia/reperfusion injury. (PubMed, Am J Pathol) - "Administration of the JNK inhibitor, CC-930, substantially reduced the severity of renal failure, tubular damage and inflammation at 24hr in a rat IRI model...Finally, primary cultures of Jnk1-/-, but not Jnk2-/-, tubular epithelial cells were protected from oxidant-induced cell death, in association with preventing phosphorylation of proteins (RIP3 and MLKL) in the necroptosis pathway. In conclusion, JNK1 but not JNK2 plays a specific role in IRI-induced cell death in the proximal tubule leading to acute renal failure."

Journal • Preclinical • Acute Kidney Injury • Immunology • Inflammation • Renal Disease • Reperfusion Injury • MAPK8

A study to characterize the safety, PK and biological activity of CC-930 in idiopathic pulmonary fibrosis (IPF) (clinicaltrials.gov) - P2, N=28; Recruiting -> Terminated (The benefit/risk profile does not support continuation of this study)

Trial termination • Fibrosis

JNK1: AN EMERGING THERAPEUTIC TARGET IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) DOWNSTREAM OF THE B-CELL RECEPTOR, WHICH OVERCOMES IBRUTINIB RESISTANCE (EHA 2019) - "JNK inhibition with the kinase inhibitors SP600125 and CC-930, the substrate binding inhibitor protein L-JNKi or siRNA mediated silencing all lead to apoptosis induction in IgVH unmutated primary human CLL samples. JNK1 inhibition was even effective in a CLL xenograft model of a patient being resistant to ibrutinib treatment. In addition to direct effects on CLL cells, we found that JNK1 inhibitors in vivo also improve T-cell responses, and reduce the frequency of immunosuppressive Tregs, while increasing the activity of CD4+ and CD8+ T-cells.Conclusion In conclusion, our studies revealed JNK1 as a promising novel therapeutic target in CLL downstream of the BCR, which can overcome ibrutinib resistance, and additionally improve immune responses against CLL cells."

IO Biomarker

Mice with established diabetes have enhanced susceptibility to renal ischaemia/reperfusion injury: role of the JNK signalling pathway (ISN-WCN 2019) - "...The aims of this study were to: (i) characterize a model of renal I/R injury in diabetic mice, and; (ii) determine if treatment with the JNK inhibitor, CC-930, can prevent the development of I/R-induced acute kidney injury in diabetic mice... Mice with established diabetes, but without overt kidney disease, have an increased susceptibility to I/R-induced acute kidney injury with enhanced JNK signalling. Prophylactic treatment with a JNK inhibitor gave substantial protection against I/R-induced renal injury in diabetic mice."

Preclinical