UM-164 / University of Michigan - LARVOL DELTA

Enhancement of antibiotic therapy in osteomyelitis by inhibiting talin-1-mediated bacterial internalization. (PubMed, Front Cell Infect Microbiol) - "By effectively inhibiting bacterial internalization, UM-164 restricted bacteria to the extracellular space, thereby synergizing with systemic gentamicin to reduce the overall bacterial burden and mitigate bone destruction in vivo. In conclusion, the structural binding of Mprip to Talin-1 and the resulting phosphorylation cascade drive S. aureus osteomyelitis through a dual mechanism of bacterial internalization and PI3K/AKT-mediated osteogenic suppression. UM-164, a small molecule specifically screened to target the Mprip/Talin-1 D125 interface, presents a potent host-directed strategy to prevent bacterial internalization and potentiate antibiotic efficacy in recalcitrant bone infections."

Journal • Infectious Disease • Inflammation • Musculoskeletal Diseases • Orthopedics • MPRIP • TLN1

LEP-AD: language embedding of proteins and attention to drugs predicts drug-target interactions. (PubMed, J Cheminform) - "In summary, our benchmark highlights the strengths and limitations of current drug-target interaction models across diverse datasets and evaluation settings. The results emphasize the impact of pretrained protein and molecular representations on predictive performance and illustrate the persistent challenges of generalization, while the modular LEP-AD framework provides a flexible reference point for comparative evaluation."

Journal

UHRF1-Mediated Epigenetic Reprogramming Regulates Glycolysis to Promote Progression of B-Cell Acute Lymphoblastic Leukemia (ASH 2023) - "In vitro experiments, knockout of gene UHRF1 promoted the cycle arrest and apoptosis of B-ALL tumor cell line (Reh and nalm6), inhibited the proliferation of cells, and improved the drug sensitivity of vindesine. Furthermore, UM164 demonstrated the ability to inhibit the proliferation of B-ALL cells both in vitro and in vivo, leading to prolonged survival in a B-ALL mouse model. In conclusion, we have unraveled the molecular mechanisms of epigenetic and metabolic rearrangements in relapsed/refractory B-ALL, and have provided potential targeted therapeutic strategies to improve its unfavorable prognosis."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • HSPB1 • IGFBP2 • UHRF1

UHRF1-mediated epigenetic reprogramming regulates glycolysis to promote progression of B-cell acute lymphoblastic leukemia. (PubMed, Cell Death Dis) - "Furthermore, we identified UM164 as a targeted inhibitor of UHRF1 that substantially inhibits P38 protein phosphorylation, downregulates HK2 expression, and reduces lactate production...In summary, our investigation revealed the molecular mechanisms of epigenetic and metabolic reprogramming in relapsed and refractory B-cell acute lymphoblastic leukemia and provides potential targeted therapeutic strategies to improve its inadequate prognosis. The schematic model showed the regulator network of UHRF1-SFRP5-WNT5A-P38 MAPK-HK2 in B-ALL."

Journal • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • UHRF1

UM-164, a Dual Inhibitor of c-Src and p38 MAPK, Suppresses Proliferation of Glioma by Reducing YAP Activity. (PubMed, Cancers (Basel)) - "UM-164 shows stronger binding to the active sites of Src compared with the conventional Src inhibitor Dasatinib. Furthermore, the in vitro anti-glioma effect mediated by UM-164 was confirmed in a xenograft glioma model. Together, these findings reveal a mechanism by which UM-164 suppresses the malignant phenotypes of glioma cells and might provide a rationale for UM-164-based anti-glioma clinical trials."

Journal • Brain Cancer • Breast Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • Triple Negative Breast Cancer • AXL • CCN1

An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2. (PubMed, Front Pharmacol) - "Among them, UM-164 exhibited the strongest binding affinity of 4.97 µM and was able to interfere with the binding of TIPE2 and PIP2 according to competitive bio-layer interferometry (BLI), which indicates that UM-164 is a potential inhibitor against TIPE2 function. The work demonstrates the feasibility of incorporating deep learning and MD simulation in virtual drug screening and provides high potential inhibitors against TIPE2 for drug development."

Journal • Inflammation • Oncology • TNFA

Retraction: UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer. (PubMed, Clin Cancer Res) - No abstract available

Journal • Preclinical

Identification of biomarkers for UM-164 in triple-negative breast cancer (AACR 2019) - "To verify our results, independently targeting the DJ1 pathway, we show that AKT inhibition results in synergy when combined with UM-164. The outcome of this research yields a robust and generalizable methodology for the identification of biomarkers in cancer to design Phase I-III trials and for generating the mechanistic evidence of effective rational combinations."

Biomarker • BRCA Biomarker • PARP Biomarker