serdemetan (JNJ-26854165) / J&J - LARVOL DELTA

Serdemetan promotes bone regeneration via coordinated regulation of osteoblast and osteoclast activity. (PubMed, Biomed Pharmacother) - "Regarding preclinical efficacy, serdemetan markedly accelerated bone healing in a rat calvarial defect model and restored trabecular bone architecture in an ovariectomy-induced osteoporosis model, demonstrating similar therapeutic efficacy to alendronate. In summary, we present serdemetan as a promising candidate for bone regeneration through regulation of the MDM2-p53 axis, offering new therapeutic possibilities beyond its established role in oncology."

Journal • Oncology • Rheumatology

Endurance training increases a ubiquitylated form of histone H3 in the skeletal muscle, supporting Notch1 upregulation in an MDM2-dependent manner. (PubMed, J Physiol) - "Serdemetan, an MDM2 ring domain inhibitor, reduced Notch1 mRNA and H3Ub level in myotubes...Training increases skeletal muscle abundance of a ubiquitylated form of H3 (H3Ub); in myotubes EZH2 inhibition limits H3Ub accumulation after contractile activity repeated over 4 days and MDM2 inhibition reduces H3Ub levels and upregulates Notch1 expression. MDM2-dependent ubiquitylation of H3 might explain why H3K27me3 enrichment fails to silence Notch1 after training; whether H3Ub is crucial to halt adaptation and establish a new muscle homeostasis requires further investigation."

Journal • Targeted Protein Degradation • KDR • MDM2 • NOTCH1

Prognostic and tumor microenvironmental features of gastric cancer revealed by macrophage polarization and protein lactylation-related genes. (PubMed, Front Genet) - "Drug sensitivity analysis highlighted AZD.0530, CCT007093, DMOG, JNJ.26854165, and LFM.A13 as promising therapeutic candidates. In both datasets, expression of prognostic genes was significantly higher in the GC cohort. This study identified ERCC6L and MYB as key prognostic genes, facilitating the development of a risk model that offers novel insights into potential therapeutic strategies for GC."

Biomarker • Journal • Gastric Cancer • Oncology • Solid Tumor • ERCC6 • MUC16 • TP53 • TTN

Identification of novel fructose 1,6-bisphosphate aldolase inhibitors against tuberculosis: QSAR, molecular docking, and molecular dynamics simulation-based analysis of DrugBank compounds. (PubMed, J Biomol Struct Dyn) - "REPTree, chosen for further screening, led to the identification of four promising preclinical anti-TB drug candidates from DrugBank-Serdemetan, Parecoxib, N, N-Diethyl-2-[(2-Thienylcarbonyl) amino], and Visnadine.All screened ligands show stable binding behaviour during a 200-ns molecular dynamics simulation. Density functional theory (DFT) analysis was also employed for the analysis HOMO (highest occupied molecular orbital)/LUMO (lowest unoccupied molecular orbital) gap, and both screened hits showed efficient results. This study presents a potential avenue for effective TB therapeutics development from compounds with proven druggability in other contexts."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

p27 Cell Cycle Inhibitor and Survival in Luminal-Type Breast Cancer: Gene Ontology, Machine Learning, and Drug Screening Analysis. (PubMed, J Breast Cancer) - "The integration of ML and bioinformatic analyses of p27 has the potential to enhance risk stratification and facilitate personalized treatment strategies for patients with breast cancer."

Journal • Machine learning • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CD8 • CDKN1A • CDKN1B • CDKN2B • ER • PGR

Analysis of the role of CHPF in colorectal cancer tumorigenesis and immunotherapy based on bioinformatics and experiments. (PubMed, Discov Oncol) - "CHPF could promote the proliferation and migration of CRC cells and lead to poor prognosis, possibly through wnt pathways as well as changes in TME. Patients with high expression of CHPF had poor efficacy in immunotherapy, which might be related to Tregs cell infiltration. Above all, it might offer more reliable guidance for future immunotherapy."

IO biomarker • Journal • Tumor mutational burden • Colorectal Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Solid Tumor • CHPF • MSI • PD-1 • TMB

In silico and in vitro assessment of drugs potentially causing adverse effects by inhibiting CYP17A1. (PubMed, Toxicol Appl Pharmacol) - "The most potent CYP17A1 inhibitors identified are serdemetan, mocetinostat, nolatrexed, liarozole, and talarozole. While some of these drugs are currently under investigation for the treatment of various cancers, their potential for the treatment of prostate cancer is yet to be explored. The DrugBank database was screened for CYP17A1 inhibitors, to increase the awareness for the risk of drug-induced pseudohyperaldosteronism and to highlight drugs so far unknown for their potential to cause side effects resulting from CYP17A1 inhibition."

Adverse events • Journal • Preclinical • Cardiovascular • Endocrine Disorders • Genito-urinary Cancer • Hypertension • Oncology • Prostate Cancer • Solid Tumor

A NOVEL IMMUNE-RELATED EPIGENETIC SIGNATURE BASED ON THE TRANSCRIPTOME FOR PREDICTING THE PROGNOSIS AND THERAPEUTIC RESPONSE OF PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA (ICML 2023) - "According to the prediction, EC1 was more sensitive to vorinostat, serdemetan and navitoclax. However, ruxolitinib, cytarabine and CP466722 were more suitable treatments for EC2... The novel immune-related epigenetic signature exhibits promising clinical predictive value for DLBCL, particularly for guiding epigenetic therapeutic regimens. R-CHOP based combination treatment regimens are suggested. Keywords: DLBCL, prognosis response, epigenetic, immune infiltration signature."

Clinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • B2M • CD70 • CD8 • KMT2D • MYD88 • TP53

A Plasmodium falciparum RING Finger E3 Ubiquitin Ligase Modifies the Roles of PfMDR1 and PfCRT in Parasite Drug Responses. (PubMed, Antimicrob Agents Chemother) - "PfRFUL KD rendered the parasites more sensitive to multiple antimalarial drugs, including mefloquine, piperaquine, amodiaquine, and dihydroartemisinin. PfRFUL KD also decreased the protein level of the P. falciparum multiple drug resistance 1 protein (PfMDR1) and altered the ratio of two bands of the P. falciparum chloroquine resistance transporter (PfCRT), suggesting contributions to the changed drug responses by the altered ubiquitination of these two molecules. The inhibition of proteasomal protein degradation by epoxomicin increased the PfRFUL level, suggesting the degradation of PfRFUL by the proteasome pathways, whereas the inhibition of E3 ubiquitin ligase activities by JNJ26854165 reduced the PfRFUL level. This study reveals the potential mechanisms of PfRFUL in modifying the expression of drug transporters and their roles in parasite drug responses. PfRFUL could be a potential target for antimalarial drug development."

Journal • Infectious Disease • Malaria • Targeted Protein Degradation • ABCB1

A novel immune-related epigenetic signature based on the transcriptome for predicting the prognosis and therapeutic response of patients with diffuse large B-cell lymphoma. (PubMed, Clin Immunol) - "According to the prediction, EC1 was more sensitive to vorinostat, serdemetan and navitoclax. However, ruxolitinib, cytarabine and CP466722 were more suitable treatments for EC2. The novel immune-related epigenetic signature exhibits promising clinical predictive value for diffuse large B-cell lymphoma (DLBCL), particularly for guiding epigenetic therapeutic regimens. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) based combination treatment regimens are suggested."

Journal • Diffuse Large B Cell Lymphoma • Gene Therapies • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • B2M • CD70 • CD8 • KMT2D • MYD88 • TP53

MDM2 inhibition as a non-hormone dependent radiosensitizing strategy in p53 wild-type breast cancer models (AACR 2022) - "In vivo efficacy of combination therapy was evaluated with CAL-51 and CAL-51 p53 CRISPR xenograft models. An MDM2 inhibitor (JNJ-26854165) was nominated as an effective drug in treatment for RT-resistant BC cell lines (R2 = 0.43, p value 10μm)... These results demonstrate the combination of RT and MDM2 inhibition may be an effective therapeutic strategy in patients with p53-wild type breast cancer, regardless of hormone receptor status."

Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • MDM2

Gain-of-Function Mutant TP53 R248Q Overexpressed in Epithelial Ovarian Carcinoma Alters AKT-Dependent Regulation of Intercellular Trafficking in Responses to EGFR/MDM2 Inhibitor. (PubMed, Int J Mol Sci) - "Previously, we have demonstrated that the combined inhibition of EGFR and MDM2-p53 pathways, by gefitinib and JNJ-26854165, exerts a strong synergistic lethal effect on HGSOC cells. Our findings suggested that the R248Q mutation of p53 in HGSOC caused significant changes in signaling protein function and trafficking, under EGFR/MDM2-targeted inhibition. Such knowledge could help to advance our understanding of the role of mutant p53 in ovarian carcinoma and to improve the prognosis of patients receiving EGFR/MDM2-targeted therapies."

Journal • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • AKT1 • EGFR • MDM2 • TP53

[VIRTUAL] The role of MDM2 inhibition in the radiosensitization of ER+ breast cancers (AACR 2021) - "yH2AX immunofluorescence was used to measure dsDNA breaks.Results​: A MDM2 inhibitor (JNJ-26854165) was nominated as an effective drug in treatment for RT-resistant BC cell lines (R2​ = 0.43, p-value <0.01) in our novel radiosensitizer screen...AMG-232 and RT combined led to an increase in apoptosis compared to RT alone in ER+ p53 WT cells but not p53 MT cells...​G1 cell cycle arrest was a secondary effect of MDM2 inhibition and radiation. Experiments investigating the role of dsDNA breaks in radiosensitization are ongoing.Conclusions​: Our novel radiosensitizer screen identifies MDM2 as a potential mediator of radioresistance in ER+ BC in a p53-dependent manner and suggests that MDM2 targeting concurrent with RT may represent a tractable clinical strategy in women with locally advanced ER+, p53 WT BC."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

EPHA5 mutation predicts the durable clinical benefit of immune checkpoint inhibitors in patients with lung adenocarcinoma. (PubMed, Cancer Gene Ther) - "In addition, patients with EPHA5 mutations tended to be more sensitive to certain targeted molecular inhibitors, including serdemetan, lox2, and PF1-1. Collectively, our results suggest that identifying mutations in the EPHA5 gene may provide insight into the genome-wide mutational burden and may serve as a biomarker to predict the immune response of patients with LUAD."

Checkpoint inhibition • Clinical • IO Biomarker • Journal • Breast Cancer • Immune Modulation • Inflammation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TMB

[VIRTUAL] A radiosensitizer screen identifies a novel role for MDM2 inhibition in the radiosensitization of ER+ breast cancers in a p53 dependent manner (AACR-II 2020) - "AlamarBlue was used to determine IC50 values of the MDM2 inhibitor AMG-232. Western blot analysis of Cleaved PARP was used to measure apoptosis and Cyclins A and E to measure cell cycle progression. Our radiosensitizer screen nominated the MDM2 inhibitor (JNJ-26854165) as one of the most effective drugs in treating RT-resistant BC cell lines (R2= 0.43, p-value <0.01)... Our novel radiosensitizer screen identifies MDM2 as a potential mediator of radioresistance in ER+ BC. Additionally, MDM2 inhibition confers radiosensitization in a p53 dependent manner in ER+ BC and may represent a tractable clinical strategy in women with p53 WT BC."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • MDM2