CPI-169 / Novartis - LARVOL DELTA

NF-κB-mediated enhancement of H3K27me3 through EZH2: a mechanism to suppress pyocyanin-induced autophagy in macrophages. (PubMed, Eur J Med Res) - "The NF-κB/EZH2/H3K27me3 axis plays a pivotal role in suppressing PYO-induced autophagy in macrophages by repressing the transcription of ULK1 and MAP1LC3B."

Journal • BECN1 • EZH2 • KDM6B • MAP1LC3B

BRD4 interacting genes as prognostic biomarkers in hepatocellular carcinoma for optimized treatment strategies. (PubMed, Sci Rep) - "Experimental validation further indicated that the combination of BRD4 inhibitor ZBC260 and EZH2 inhibitor CPI-169 synergistically enhanced apoptosis in HCC. Collectively, this study provides a scientific rationale for early HCC diagnosis and personalized therapy, offering new insights into drug resistance in treatment."

Biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • BRD4 • KIF20A • KIF2C

YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2Y641mut germinal center-derived lymphoma. (PubMed, Neoplasia) - "Here we undertook the simultaneous evaluation of two epigenetic drugs targeting EZH2 methyltransferase activity and BRD4-mediated control of MYC transcription, CPI169 and CPI203, using preclinical models of DLBCL and FL with distinct EZH2 mutational status. Gene expression profile, exploratory data analysis, and siRNA screening identified the PI3K/AKT-regulated gene and mitosis regulator, YPEL2, as a crucial factor involved in the efficacy of MYC/EZH2 dual targeting both in vitro and in vivo. Altogether, our results provide first pre-clinical evidence that simultaneous targeting of MYC and EZH2 is a safe and efficient approach that can be monitored by specific biomarkers, in aggressive lymphoid tumors of germinal center origin."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BRD4 • PI3K • YPEL2

Thiol-Reactive or Redox-Active: Revising a Repurposing Screen Led to a New Invalidation Pipeline and Identified a True Noncovalent Inhibitor Against Papain-like Protease from SARS-CoV-2. (PubMed, ACS Pharmacol Transl Sci) - "Using a screening-based approach to identify inhibitors of PLpro's proteolytic activity, we made extensive efforts to validate active compounds over a range of conditions and readouts, emphasizing the need for comprehensive orthogonal data when profiling putative PLpro inhibitors. The remaining active compound, CPI-169, was shown to be a noncovalent inhibitor capable of competing with GRL-0617 in NMR-based experiments, suggesting that it occupied a similar binding site and inhibited viral replication in Vero-E6 cells, opening new design opportunities for further development as antiviral agents."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling. (PubMed, J Exp Clin Cancer Res) - "Collectively, our study highlighted the potential of the therapeutic combination of FGFR4 and EZH2 inhibitors, which would provide new references for the further development of clinical treatment strategies for HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • EZH2 • FGFR4

YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2-mutated germinal center-derived lymphoma. (EACR 2022) - "Given the known interplay between EZH2 and MYC downstream signaling in malignant B cells, we undertook the simultaneous evaluation of two epigenetic drugs that interfere with EZH2 methyltransferase activity and BRD4-mediated control of MYC transcription, namely CPI169 and CPI203; using preclinical models of DLBCL and FL with distinct EZH2 mutational status. Gene expression profile analysis, followed by automated exploratory data analysis and validation by a siRNA screening, further identified the PI3K/AKT-regulated gene and mitosis regulator, YPEL2; as a crucial factor involved in the efficacy of MYC/EZH2 dual targeting in vitro and in vivo . Conclusion These results provide a first preclinical evidence that simultaneous targeting of MYC and EZH2 is a safe and efficient approach that can be monitored by specific biomarkers in aggressive lymphoid tumors of germinal center origin."

Clinical • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • BRD4 • EZH2 • PI3K • YPEL2