CEP-1347 / Teva, Lundbeck, Kyowa Kirin - LARVOL DELTA

Mixed lineage kinase 3 contributes to myocardial ischemia/reperfusion injury by regulating neutrophil activation. (PubMed, Basic Res Cardiol) - "Furthermore, treatment with CEP-1347, a small-molecule MLK3 inhibitor, attenuated myocardial injury, reduced apoptosis, and limited adverse remodeling in vivo. In acute myocardial infarction (AMI) patients, elevated levels of phosphorylated MLK3 (pMLK3) in circulating neutrophils were associated with increased levels of MPO-DNA, cTnT, and CK-MB, as well as a trend toward higher rates of cardiovascular rehospitalization. These findings identify a neutrophil-intrinsic MLK3-C/EBPβ-CRAMP axis that amplifies myocardial inflammation and injury, and suggest MLK3 as a promising therapeutic target and potential biomarker for ischemic heart disease."

Journal • Cardiovascular • Coronary Artery Disease • Heart Failure • Inflammation • Myocardial Infarction • Myocardial Ischemia • Reperfusion Injury • MAP3K11

Senolytic Elimination of Senescent Ovarian Clear Cell Carcinoma Cells Induced by CEP-1347 With the BH3 Mimetic Navitoclax. (PubMed, Anticancer Res) - "CEP-1347 induced cellular senescence in OCCC cells with wild-type TP53. The combination of CEP-1347 with senolytics, such as navitoclax, represents a rational strategy to ensure the selective elimination of senescent OCCC cells and enhance therapeutic efficacy."

Journal • Brain Cancer • Clear Cell Carcinoma • Epithelial Ovarian Cancer • Glioma • Oncology • Ovarian Cancer • Ovarian Clear Cell Cancer • Solid Tumor • MDM4

The MDM4 Inhibitor CEP-1347 Activates Wild-type p53 in Ovarian Clear Cell Carcinoma Cells and Potently Inhibits their Growth. (PubMed, Anticancer Res) - "The present results suggest the potential of targeting MDM4 with CEP-1347 as a therapeutic approach for the treatment of OCCC with wild-type p53."

Journal • P53WT • Clear Cell Carcinoma • Oncology • Ovarian Cancer • Ovarian Clear Cell Cancer • Solid Tumor • CDKN1A • MDM4

MLKs Inhibitor CEP-1347 Suppresses Tumorigenic Potential and Survival of Colon Cancer Cells (ACS-CLINCON 2025) - "CEP-1347 effectively inhibits MLK4 kinase activity in colon cancer cells, leading to increased apoptosis and reduced migratory potential. These findings suggest that MLK4 inhibition may be a promising therapeutic strategy for treating intractable colon cancers unresponsive to current therapeutic approaches."

IO biomarker • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • BAX • BCL2 • CASP3 • MAP3K21

Targeting Bcl-xL with Navitoclax Effectively Eliminates Senescent Tumor Cells That Appear Following CEP-1347-Induced Differentiation of Glioma Stem Cells. (PubMed, Int J Mol Sci) - "The knockdown of Bcl-xL resulted in more pronounced GSC death in combination with CEP-1347 than that of Bcl-2. These results suggest that combining CEP-1347 with the targeting of Bcl-xL, the expression of which increases with CEP-1347-induced senescence, is a rational approach to ensure the elimination of GSCs, thereby improving the outcomes of glioblastoma treatment."

IO biomarker • Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • BCL2 • BCL2L1

SELECTIVE DEGRADATION OF MLK3 BY NOVEL CEP1347-VHL-02 PROTAC COMPOUND LIMITS ONCOGENIC POTENTIAL OF TNBC (EACR 2025) - "In conclusion, we present first-in-class PROTAC that induces the rapid and selective degradation of MLK3 in cancer cell lines. Our study provides new opportunities for the selective targeting of MLK3 in cancer and paves the way for the development of next-generation degraders against MLK3 and related kinases. Notably, MLK3 degradation by CEP1347-VHL-02 significantly reduced the oncogenic potential of TNBC cells, suggesting that the targeted degradation of this kinase may be a feasible treatment strategy for this subtype of breast cancer."

Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • Von Hippel-Lindau Syndrome • MAP3K11

Novel MDM4 Inhibitor CEP-1347-based therapy for p53 wild-type malignant meningioma (SNO 2024) - "The small-molecule MDM2 inhibitor RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. [Conclusion] Our findings suggest that targeting the p53 pathway with CEP-1347 is a novel and viable approach to treating aggressive meningiomas, with even greater efficacy when combined with MDM2 inhibitors."

Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • MDM4

Prognostic Value of Parkinson’s Disease Subtypes in the LABS-PD Cohort: Functional ability, Quality of life and Mortality (MDS Congress 2024) - " To identify PD subtypes, we conducted cluster analyses in the LABS-PD cohort with 461 PD patients enrolled in the randomized controlled trial CEP-1347 (PRECEPT) within two years of diagnosis, followed for at least five years... PD subtypes generated in LABS-PD have some prognostic value for short-term functional ability and long-term survival. Membership to the "Tremor Predominant" subtype at 5 years after PD diagnosis was associated with preserved functional ability and longer survival compared to the "Motor Complications" subtype, particularly for those >65 years. Future work should focus on replicating the results in independent cohorts and validating clinical applicability at individual level."

HEOR • CNS Disorders • Parkinson's Disease

CEP-1347 Boosts Chk2-Mediated p53 Activation by Ionizing Radiation to Inhibit the Growth of Malignant Brain Tumor Cells. (PubMed, Int J Mol Sci) - "CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. The present results show, for the first time, that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR in addition to inhibiting the expression of MDM4 and, thus, CEP-1347 has potential as a radiosensitizer for malignant brain tumors expressing wild-type p53."

Journal • Tumor cell • Brain Cancer • CNS Tumor • Glioma • Meningioma • Oncology • Solid Tumor • CHEK2 • MDM4

Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC. (PubMed, J Med Chem) - "Furthermore, we showed that CEP1347-VHL-02 robustly degraded MLK3 and inhibited its oncogenic activity in TNBC, measured as a reduction of clonogenic and migratory potential, cell cycle arrest, and the induction of apoptosis in MDA-MB-468 cells. In conclusion, we present CEP1347-VHL-02 as a novel MLK3 degrader that may be a promising new strategy to target MLK3 in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • Von Hippel-Lindau Syndrome • MAP3K11

CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells. (PubMed, Cancers (Basel)) - "These data suggest that there exists a hitherto unrecognized interaction between MDM4 and PKC to inactivate the p53-dependent growth control in UM cells. CEP-1347, which dually targets MDM4 and PKC, could therefore be a promising therapeutic candidate in the treatment of UM."

Journal • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • MDM4

CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells (Multidisciplinary Digital Publishing Institute) - "The results showed that, at its clinically relevant concentrations, CEP-1347 reduced not only MDM4 expression but also PKC activity, activated the p53 pathway, and effectively inhibited the growth of UM cells. Importantly, whereas inhibition of either MDM4 expression or PKC activity alone failed to efficiently activate p53 and inhibit cell growth, inhibition of both resulted in effective activation of p53 and inhibition of cell growth."

Preclinical • Uveal Melanoma

Antagonizing MDM2 Overexpression Induced by MDM4 Inhibitor CEP-1347 Effectively Reactivates Wild-Type p53 in Malignant Brain Tumor Cells. (PubMed, Cancers (Basel)) - "Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest the combination of CEP-1347-induced MDM2 overexpression with the selective inhibition of MDM2's interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells."

Journal • Tumor cell • Brain Cancer • CNS Tumor • Glioma • Meningioma • Oncology • Solid Tumor • MDM2 • MDM4

The Novel MDM4 Inhibitor CEP-1347 Activates the p53 Pathway and Blocks Malignant Meningioma Growth In Vitro and In Vivo. (PubMed, Biomedicines) - "CEP-1347 effectively inhibited the growth of malignant meningioma xenografts at a dose that was far lower than the maximum dose that could be safely given to humans. Our findings suggest targeting the p53 pathway with CEP-1347 represents a novel and viable approach to treating aggressive meningiomas."

Journal • Preclinical • Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • MDM4

The emerging role of mixed lineage kinase 3 (MLK3) and its potential as a target for neurodegenerative diseases therapies. (PubMed, Eur J Med Chem) - "In fact, one MLK3 inhibitor, CEP-1347, reached clinical trials for Parkinson's disease. Additionally, another compound called prostetin/12k, a potent and rather selective MLK3 inhibitor has started clinical development for ALS based on its motor neuron protection in both in vitro and in vivo models. In this review, we will focus on the role of MLK3 in neuron-related cell death processes, neurodegenerative diseases, and the potential advantages of targeting this kinase through pharmacological modulation for neuroprotective treatment."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Movement Disorders • Parkinson's Disease • MAP3K11

TrkA expression directs the anti-neoplastic activity of MLK3 inhibitors in triple-negative breast cancer. (PubMed, Oncogene) - "Knockdown of MLK3 or MLK3 inhibitors, CEP-1347 and URMC-099, attenuated tumorigenesis of TNBC cell line and Patient-Derived (PDX) xenografts. The TNBC cell line unresponsive to kinase inhibitor had substantially lower TrkA, and overexpression of TrkA restored the sensitivity to MLK3 inhibition. These results suggest that the functions of MLK3 in breast cancer cells depend on downstream targets in TNBC tumors expressing TrkA, and MLK3 kinase inhibition may provide a novel targeted therapy."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MAP3K11

CEP-1347 Targets MDM4 Protein Expression to Activate p53 and Inhibit the Growth of Glioma Cells. (PubMed, Anticancer Res) - "Our findings suggest CEP-1347 is a novel inhibitor of MDM4 protein expression and as such activates p53 to inhibit the growth of cancer cells with wild-type p53, including retinoblastoma and glioblastoma."

Journal • Brain Cancer • CNS Disorders • CNS Tumor • Eye Cancer • Glioblastoma • Glioma • Movement Disorders • Oncology • Parkinson's Disease • Retinal Disorders • Retinoblastoma • Solid Tumor • MDM4 • TP53

Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts. (PubMed, Int J Mol Sci) - "In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • Transplantation

p70 ribosomal protein S6 kinase is a checkpoint of human hepatic stellate cell activation and liver fibrosis in mice. (PubMed, Cell Mol Gastroenterol Hepatol) - "We establish p70S6K as a checkpoint of fibrogenesis in vitro and in vivo and CEP-1347 as potential treatment option which can safely be used for long-term treatment."

Journal • Preclinical • Fibrosis • Gastroenterology • Gastrointestinal Cancer • Hepatology • Immunology • Liver Cancer • Liver Cirrhosis • Oncology • Solid Tumor • RPS6

Mixed Lineage Kinase 3 phosphorylates prolyl-isomerase PIN1 and potentiates GLI1 signaling in pancreatic cancer development. (PubMed, Cancer Lett) - "Additionally, pharmacological inhibition of MLK3 by CEP-1347 promoted apoptosis in PDAC cell lines, reduced tumor burden, extended survival, and reduced GLI1 expression in the Pdx1-Cre x LSL-KRAS x LSL-TP53 (KPC) mouse model of PDAC. These findings collectively suggest that MLK3 is an important regulator of oncogenic GLI1 and that therapies targeting MLK3 warrant consideration in the management of PDAC patients."

Journal • Brain Cancer • Gastrointestinal Cancer • Glioma • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • GLI1 • KRAS • MAP3K11 • TP53

MAP3K11 regulates hedgehog signaling and suppresses tumor microenvironment in genetic mouse models of pancreatic cancer (AACR 2018) - "...Interestingly, MLK3 was able to directly phosphorylate Gli1 on specific residues and the transcriptional activity of Gli1 was synergistically regulated by Pin1 and MLK3 together, which was partially blocked by pan-MLK inhibitor, CEP-1347...In conclusion, our findings suggest that pathological activation of MLK3-Pin1 axis could promote survival of pancreatic cancer cells via Hh pathway activation. Collectively our results suggest that targeting MLKs could be an alternative approach to overcome Desmoplasia and PDAC."

Tumor microenvironment • Pancreatic Cancer

Elucidating the role of mixed lineage kinase 3 (MLK3)--catenin axis in hepatocellular carcinoma (AACR 2018) - "...However, the only therapeutic option currently available for advanced HCCs is Sorafenib which is only effective for a few months...To obtain a broader picture on the potential effects of MLK3 in HCC disease progression, studies were performed with HCC cell lines following treatment with a pan MLK inhibitor CEP-1347 (CEP)...Further validationfollowing siRNA-mediated knockdown of MLK3 showed a potentiation of the apoptotic response following CEP treatment. Taken together these findings indicate that MLK3 plays a major role in HCC progression and CEP-induced targeting of this axis might be efficacious in the management of HCC."

IO Biomarker • PARP Biomarker • Hepatocellular Cancer

Identification of genes required for enzalutamide resistance in castration-resistant prostate cancer cells in vitro. (PubMed, Mol Cancer Ther) - "Knockdown of MAP3K11 reduced cell survival and pharmacologic inhibition of MAP3K11 with CEP-1347 in combination with enzalutamide resulted in a dramatic increase in cell death. Finally, while PSMD12 expression did not change during disease progression, knockdown of PSMD12 resulted in decreased AR and AR splice variant expression, likely contributing to the C4-2B and 22Rv1 decrease in cell survival. Our study has therefore identified at least three new supporters of enzalutamide resistance in castration-resistant prostate cancer cells in vitro."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • SPDEF

[VIRTUAL] p70S6K IS A CHECKPOINT OF FIBROGENESIS IN HUMAN HEPATIC STELLATE CELLS WHICH CAN BE EFFECTIVELY INHIBITED BY THE CLINICALLY VIABLE KINASE INHIBITOR CEP-1347 (AASLD 2020) - "p70S6K signaling is dysregulated in human liver cirrhosis and during activation of phHSC. The inhibition of p70S6K results in an inhibition of HSC activation. We identified CEP-1347 as a p70S6K inhibitor that blocks important features of the profibrotic behavior in HSC."

Clinical • CNS Disorders • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis • Movement Disorders • Parkinson's Disease

Inhibition of Retinoblastoma Cell Growth by CEP1347 Through Activation of the P53 Pathway. (PubMed, Anticancer Res) - "We propose CEP1347 as a promising candidate for the treatment of retinoblastomas, where functional inactivation of P53 as a result of MDM4 activation is reportedly common."

Journal • CNS Disorders • Movement Disorders • Oncology • Parkinson's Disease • Retinal Disorders • Solid Tumor