CHR-6494 / Kansai Medical University - LARVOL DELTA

Design, synthesis, and in vitro anti-renal fibrotic effects of imidazopyridazine-based homeodomain-interacting protein kinase 2 inhibitors. (PubMed, Bioorg Med Chem) - "We developed compound c4 through rational optimization of the lead compound CHR-6494...Functional assays in TGF-β-stimulated NRK-49F cells and TNF-α-stimulated HK-2 cells demonstrated that c4, even at low concentrations, significantly downregulated fibrosis markers (Collagen I, Fibronectin, α-SMA) and inflammatory mediators (p-P65, IL-6), while suppressing fibrotic responses (cell proliferation, migration). These findings establish c4 as a promising HIPK2 kinase inhibitor for developing effective anti-fibrotic therapies targeting HIPK2 in CKD."

Journal • Preclinical • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • FN1 • IL6 • SMAD3 • TGFB1 • TNFA

Targeting HASPIN kinase disrupts SR protein-mediated RNA splicing and synergizes with BCL-2 inhibitor venetoclax in AML. (PubMed, Blood Neoplasia) - "Furthermore, a novel combination therapy consisting of CHR-6494 and B-cell lymphoma 2 (BCL-2) inhibitor venetoclax synergistically reduced AML cell viability and resensitized venetoclax-resistant AMLs to treatment. Our study presents HASPIN kinase as a novel therapeutic target for AML, underscores an underappreciated role of HASPIN in splicing regulation, and proposes a viable combination treatment for clinical testing."

Journal • Acute Myelogenous Leukemia • B Cell Lymphoma • Leukemia • Lymphoma • Oncology

Haspin kinase inhibition dampens pseudorabies virus infection in vitro. (PubMed, Front Vet Sci) - "Additionally, treatment with CHR-6494 effectively restricted Herpes simplex virus type 1 infection in Vero cells. Collectively, these findings indicate that Haspin may serve as a novel therapeutic target for the management of infections caused by Alphaherpesvirinae."

Journal • Preclinical • Herpes Simplex • Infectious Disease • HASPIN

Virtual Screening, Molecular Dynamics, and Mechanism Study of Homeodomain-Interacting Protein Kinase 2 Inhibitor in Renal Fibroblasts. (PubMed, Pharmaceuticals (Basel)) - " The study highlights the dual functionality of HIPK2 kinase inhibitors like CHR-6494 and Abemaciclib as promising therapeutic candidates for renal fibrosis and inflammation. The findings provide new insights into HIPK2 inhibition mechanisms and suggest pathways for the design of novel HIPK2 inhibitors in the future."

Journal • Fibrosis • Immunology • Inflammation • FN1 • SMAD3 • TGFB1

Novel inhibitors targeting the PGK1 metabolic enzyme in glycolysis exhibit effective antitumor activity against kidney renal clear cell carcinoma in vitro and in vivo. (PubMed, Eur J Med Chem) - "Our previous research has revealed phosphoglycerate kinase 1 (PGK1) enhances tumorigenesis and sorafenib resistance of kidney renal clear cell carcinoma (KIRC) by regulating glycolysis, so that PGK1 is a promising drug target. Z57346765 induced expression changes of genes related to cell metabolism, DNA replication and cell cycle. Overall, we screened two novel PGK1 inhibitors, CHR-6494 and Z57346765, for the first time and discovered their potent anti-KIRC effects by suppressing PGK1 metabolic enzyme activity in glycolysis."

Journal • Preclinical • Clear Cell Renal Cell Carcinoma • Oncology • Renal Cell Carcinoma • Solid Tumor • PGK1

The Serine/Threonine Kinase HASPIN Is a Novel Dependency in t(8; 21) AML (ASH 2022) - "Finally, to assess therapeutic potential of HASPIN inhibition, t(8; 21) AML cells and healthy human CD34+ hematopoietic progenitor cells were treated with titrated HASPIN inhibitor, CHR-6494... To identify novel kinase dependencies in t(8; 21) AML, we employed a human kinase domain targeted CRISPR screen in two t(8; 21) AML cell lines (Kasumi-1 and SKNO-1). HASPIN was identified as one of the top hits that dropped out at levels comparable to positive controls, including ribosomal proteins, RNA/DNA polymerases, cell cycle regulators, and other housekeeping genes. HASPIN dependency was further validated in both t(8; 21) AML cell lines using two unique sgRNAs."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34

Co-inhibition of Aurora A and Haspin kinases enhances survivin blockage and p53 induction for mitotic catastrophe and apoptosis in human colorectal cancer. (PubMed, Biochem Pharmacol) - "Co-treatment of CHR6494 and MLN8237 enhanced the blockage of human CRC xenograft tumors in nude mice. Taken together, co-inhibition of Aurora A and Haspin enhances survivin inhibition, p53 pathway induction, mitotic catastrophe, apoptosis and tumor inhibition that may provide a potential strategy for CRC therapy."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BIRC5 • HASPIN

Inhibitory Effect of the HASPIN Inhibitor CHR-6494 on BxPC-3-Luc, A Luciferase-Expressing Pancreatic Cancer Cell Line. (PubMed, Cell J) - "Here, we reported that administration of the HASPIN inhibitor, CHR-6494, to mice bearing pancreatic BxPC-3-Luc cancer cells significantly suppressed growth of BxPC-3-Luc cells. CHR-6494 might be a useful agent for treating pancreatic cancer."

Journal • Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor