Targeted cancer therapies by means of small molecules or antibodies act on specific molecular targets to block cancer growth and progression. Kinases have become attractive molecular targets for the treatment of numerous cancer types; hence the U.S. Food and Drug Administration (FDA) has approved many small-molecule kinase inhibitors for clinical use, some of them irreversible inhibitors. Similarly, given the importance of epigenetic marks in tumorigenesis, modifiers of DNA or histones have become attractive therapeutic targets; currently, there are 6 epigenetic drugs clinically approved for cancer treatment by the FDA. In collaboration with Óscar Fernández-Capetillo, we recently started an early drug discovery project to develop SETD8 inhibitors, as non-advanced inhibitors have been described so far. By developing a non-radioactive assay, we have been able to perform a screening campaign and identify several molecules as starting points to obtain good SETD8 inhibitors that are both reversible and irreversible.
- María Elena Hernández
- Mª Isabel Albarrán
- Antonio Cebriá
- Elena Gómez-Casero
- Javier Klett
- (2021). Omipalisib inspired macrocycles as dual PI3K/mTOR inhibitors.. Eur J Med Chem 211, 113109. CNIO Publication.
- (2021). Screening health-promoting compounds for their capacity to induce the activity of FOXO3. J Gerontol A-Biol (in press). CNIO Publication.
- (2021). Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC.. Cancers 13, 2139. CNIO Publication.
- (2021). Macrocyclization as a source of desired polypharmacology. Discovery of triple PI3K/mTOR/PIM inhibitors.. ACS Med Chem Lett 12, 1794-1801. CNIO Publication.
- (2020). Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases. Nat Cell Biol 22, 1223-1238. CNIO Publication.
- (2020). The mTOR pathway is necessary for survival of mice with short telomeres.. Nat Commun 11, 1168. CNIO Publication. Open Access
- (2020). Anti?tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL?302 in neuroblastoma. EMBO Mol Med 12, e11749. CNIO Publication.
- (2020). Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas. Proc Natl Acad Sci USA 117, 24415-24426. CNIO Publication.
- (2020). Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer.. Oncogene 39, 3028-3040. CNIO Publication.
- (2020). Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells. Cancers 12, 1790. CNIO Publication. Open Access
- (2020). Pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives as CDK8 inhibitors.. Eur J Med Chem 201, 112443. CNIO Publication.
- (2020). Screening protocol for the identification of modulators by immunofluorescent cell-based assay. Chem Biol Drug Des 95, 66-78. CNIO Publication.
- (2019). The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status.. Nat Commun 10, 5428. CNIO Publication. Open Access
- (2019). Multiple cancer pathways regulate telomere protection.. EMBO Mol Med 11, e10292. CNIO Publication. Open Access
- (2019). Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma.. EMBO Mol Med 11, e10058. CNIO Publication. Open Access
- (2019). Lysosomal trapping of palbociclib and its functional implications. Oncogene 38, 3886-3902. CNIO Publication.
- (2019). Discovery of novel triazolo[4,3-b]pyridazin-3-yl-quinoline derivatives as PIM inhibitors. Eur J Med Chem 168, 87-109. CNIO Publication.
- (2019). Disulfide Engineered Lipase to Enhance the Catalytic Activity: A Structure-Based Approach on BTL2.. Int J Mol Sci 20, E5245. CNIO Publication. Open Access
- (2018). STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nat Med 24, 1024-1035. CNIO Publication.
- (2018). Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies. Clin Cancer Res 24, 3550-3559. CNIO Publication.
- (2017). Inhibition of Trf1 telomere protein impairs tumor initiation and progression in glioblastoma multiform mouse models and patient-derived xenografts. Cancer Cell 32, 590-607. CNIO Publication.
- (2017). Modulation of telomere protection by the PI3K/AKT pathway. Nat Commun 8, 1278. CNIO Publication. Open Access
- (2017). Inflammation and stem markers association to PIM1/PIM2 kinase-induced tumors in breast and uterus. Oncotarget 8, 58872-58886. CNIO Publication.
- (2017). Identification of novel PI3K inhibitors through a scaffold hopping strategy. Bioorg Med Chem Lett 27, 4794-4799. CNIO Publication.
- (2017). Generation of tricyclic imidazo[1,2-a]pyrazines as novel PI3K inhibitors by application of a conformational restriction strategy. Bioorg Med Chem Lett 27, 2536-2543. CNIO Publication.