Hepatocellular carcinoma (HCC) is a very aggressive disease and represents the third leading cause of cancer-related mortality worldwide. 5 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, SpainĪmaia Lujambio, Department of Oncological Sciences, Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue 6-111, New York, NY 10029, USA.4 Liver Cancer Translational Research Laboratory, Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit and Pathology Department, IDIBAPS, Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain.3 Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, USA.2 Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.1 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.More careful analysis of the structure-activity-relationship (SAR) of these legacy compounds is necessary to draw useful lessons for new M4K compound design.įor experimental methods and details, please visit my Zenodo post.Ĭategories ACVR1/ALK2, Brain Tumours, Diffuse intrinsic pontine glioma, Jong Fu Wong, SGC Univ. Differentially increasing the potency towards ALK2 while minimising ALK5 potency is highly desirable for future M4K designs. However, in all cases, potency towards ALK2 and ALK5 appeared to be coupled. This shows that the legacy compounds designed for FOP treatment had been well designed to minimise the risk of cardiac toxicity. Among them M4K1046 has an ALK5 IC50 of 63nM. The off-target ALK5 inhibition by most of the legacy ACVR1/ALK2 inhibitors are not high. IC50 values estimated by GraphPad Prism are shown in red. Chemical structures and DLA IC50 curves of the last 6 legacy ACVR1/ALK2 inhibitors.
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