Hansen, Finn Kristian 照片

Hansen, Finn Kristian

Professor

所属大学: University of Bonn

所属学院: Department of Pharmaceutical Chemistry

邮箱:
finn.hansen@uni-bonn.de

个人主页:
https://www.pharma.uni-bonn.de/www/pharmchem2

研究领域

The Hansen group mainly works in the field of epigenetic drug discovery. In addition to classic organic synthesis, we are currently using various modern synthetic methods such as solid-phase synthesis, microwave synthesis and multicomponent reactions. Subsequent to the synthesis, we screen the activity of the synthesized compounds in target-based biochemical assays. This allows for a fast feedback on structure-activity relationships during the optimization cycles. Our general research focus lies on the development of new tool compounds that are capable of reverting chemoresistance in cancer. To this end, promising compounds are assessed in different in vitro tumor models (e. g. antiproliferative effects, induction of apoptosis, and effects on cell cycle). Additional in-depth evaluation of biological and structural properties (including synergism experiment, in vivo studies, and X-ray crystallography) takes place in collaborating research groups across the globe. Over the last years, our group has gained broad experience in developing histone deacetylase (HDAC) inhibitors. As important modifiers of the histone structure and non-histone proteins, HDACs regulate gene expression and other pathways with effects on cellular events including the cell cycle, angiogenesis, cytoskeleton formation, protein degradation, and resistance to chemotherapy. Overexpressed in several tumor types, HDACs have been identified as valuable drug targets for targeted cancer therapy. Besides their potential as targets for single-agent drugs, HDACs are also known to participate in synergistic pathways with several other drug targets, including BET proteins, the 26S proteasome, and Hsp90. This implicates the excellent suitability of HDAC inhibitors for combination therapies but collides with the complications of polypharmacy. To overcome these drawbacks, we utilize the advantages of polypharmacology and aim at designing dual-targeting inhibitors that are capable of inhibiting two synergistic drug targets. Beyond the field of cancer, our research on small-molecule HDAC inhibitors also specializes in the development of antimalarial agents. In this regard, we are particularly interested in identifying compounds with activity against multiple malaria parasite life cycle stages that might ultimately provide drug candidates with causal prophylactic and/or transmission blocking properties. In another research area, we are interested in proteolysis-targeting chimeras (PROTACs) as a new class of chimeric small molecules. PROTACs are bifunctional modalities that are able to hijack the cellular protein degradation system by recruiting the protein of interest (POI) to E3 ubiquitin ligases, thus leading to polyubiquitinylation of the POI and induction of its proteasomal degradation. However, the synthesis of PROTACs is usually cumbersome and involves multi-step protocols due to the high molecular weight and bifunctional nature of the compounds. Hence, we are currently developing efficient solid-phase supported protocols for the synthesis of protein degrader libraries.

近期论文

Alves Avelar, LA, Schrenk, C, Sönnichsen, M, Hamacher, A, Hansen, FK, Schliehe-Diecks, J, Borkhardt, A, Bhatia, S, Kassack, MU, and Kurz, T (2021).Synergistic induction of apoptosis in resistant head and neck carcinoma and leukemia by alkoxyamide-based histone deacetylase inhibitors European Journal of Medicinal Chemistry, 211. Jenke, R, Reßing, N, Hansen, FK, Aigner, A, and Büch, T (2021).Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives Cancers, 13(4):634. Mackwitz, MK, Hesping, E, Eribez, K, Schöler, A, Antonova-Koch, Y, Held, J, Winzeler, EA, Andrews, KT, and Hansen, FK (2021).Investigation of the in vitro and in vivo efficacy of peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity European Journal of Medicinal Chemistry, 211. Pflieger, M, Sönnichsen, M, Horstick-Muche, N, Yang, J, Schliehe-Diecks, J, Schöler, A, Borkhardt, A, Hamacher, A, Kassack, MU, Hansen, FK, Bhatia, S, and Kurz, T (2021).Oxa analogues of nexturastat A demonstrate improved HDAC6 selectivity and superior anti-leukaemia activity ChemMedChem, n/a(n/a). Sinatra, L, Kolano, L, Icker, M, Fritzsche, SR, Volke, D, Gockel, I, Thieme, R, Hoffmann, R, and Hansen, FK (2021).Hybrid Peptides Based on α-Aminoxy Acids as Antimicrobial and Anticancer Foldamers ChemPlusChem, n/a(n/a). Benedetti, R, Conte, M, Dell'Aversana, C, Hansen, FK, and Zwergel, C (2020).Editorial: Chemical Innovative Approaches in Cancer Molecular Medicine and Translational Clinical Research Frontiers in Chemistry, 8:820. Friedrich, A, Assmann, AS, Schumacher, L, Stuijvenberg, JV, Kassack, MU, Schulz, WA, Roos, WP, Hansen, FK, Pflieger, M, Kurz, T, and Fritz, G (2020).In vitro assessment of the genotoxic hazard of novel hydroxamic acid-and benzamide-type histone deacetylase inhibitors (HDACi) International Journal of Molecular Sciences, 21(13):1--21. Moita, AJR, Bandolik, JJ, Hansen, FK, Kurz, T, Hamacher, A, and Kassack, MU (2020).Priming with HDAC Inhibitors Sensitizes Ovarian Cancer Cells to Treatment with Cisplatin and HSP90 Inhibitors International Journal of Molecular Sciences, 21:8300. Reßing, N, Sönnichsen, M, Osko, JD, Schöler, A, Schliehe-Diecks, J, Skerhut, A, Borkhardt, A, Hauer, J, Kassack, MU, Christianson, DW, Bhatia, S, and Hansen, FK (2020).Multicomponent Synthesis, Binding Mode, and Structure–Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups Journal of Medicinal Chemistry, 63:10339-10351. Sinatra, L, Bandolik, JJ, Roatsch, M, Sönnichsen, M, Schoeder, CT, Hamacher, A, Schöler, A, Borkhardt, A, Meiler, J, Bhatia, S, Kassack, MU, and Hansen, FK (2020).Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual-Targeting HDAC Inhibitors and HDAC Degraders (PROTACs) Angewandte Chemie - International Edition:DOI: 10.1002/anie.202006725. Erdeljac, N, Bussmann, K, Schöler, A, Hansen, FK, and Gilmour, R (2019).Fluorinated Analogues of the Histone Deacetylase Inhibitor Vorinostat (Zolinza): Validation of a Chiral Hybrid Bioisostere, BITE ACS Medicinal Chemistry Letters, 10(9):1336--1340. Koehne, E, Kreidenweiss, A, Manego, RZ, Mccall, M, Mombo-ngoma, G, Karl, M, Mackwitz, W, Hansen, FK, and Held, J (2019).Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults Scientific reports, 9:17336. Krieger, V, Hamacher, A, Cao, F, Stenzel, K, Gertzen, CGW, Schäker-Hübner, L, Kurz, T, Gohlke, H, Dekker, FJ, Kassack, MU, and Hansen, FK (2019).Synthesis of Peptoid-Based Class I-Selective Histone Deacetylase Inhibitors with Chemosensitizing Properties Journal of Medicinal Chemistry, 62:11260-11279. Mackwitz, MKW, Hesping, E, Antonova-Koch, Y, Diedrich, D, Woldearegai, TG, Skinner-Adams, T, Clarke, M, Schöler, A, Limbach, L, Kurz, T, Winzeler, EA, Held, J, Andrews, KT, and Hansen, FK (2019).Structure–Activity and Structure–Toxicity Relationships of Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity ChemMedChem, 14(9):912--926. Raudszus, R, Nowotny, R, Gertzen, CGW, Schöler, A, Krizsan, A, Gockel, I, Kalwa, H, Gohlke, H, Thieme, R, and Hansen, FK (2019).Fluorescent analogs of peptoid-based HDAC inhibitors: Synthesis, biological activity and cellular uptake kinetics Bioorganic and Medicinal Chemistry, 27:115039. Reßing, N, Marquardt, V, Gertzen, CGW, Schöler, A, Schramm, A, Kurz, T, Gohlke, H, Aigner, A, Remke, M, and Hansen, FK (2019).Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity MedChemComm, 10(7):1109--1115. Bhatia, S, Diedrich, D, Frieg, B, Ahlert, H, Stein, S, Bopp, B, Lang, F, Zang, T, Kröger, T, Ernst, T, Kögler, G, Krieg, A, Lüdeke, S, Kunkel, H, Rodrigues Moita, AJ, Kassack, MU, Marquardt, V, Opitz, FV, Oldenburg, M, Remke, M, Babor, F, Grez, M, Hochhaus, A, Borkhardt, A, Groth, G, Nagel-Steger, L, Jose, J, Kurz, T, Gohlke, H, Hansen, FK, and Hauer, J (2018).Targeting HSP90 dimerization via the C terminus is effective in imatinib-resistant CML and lacks the heat shock response Blood, 132(3):307--320. Bhatia, S, Krieger, V, Groll, M, Osko, JD, Reßing, N, Ahlert, H, Borkhardt, A, Kurz, T, Christianson, DW, Hauer, J, and Hansen, FK (2018).Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor Journal of Medicinal Chemistry, 61:10299--10309. Diedrich, D, Stenzel, K, Hesping, E, Antonova-Koch, Y, Gebru, T, Duffy, S, Fisher, G, Schöler, A, Meister, S, Kurz, T, Avery, VM, Winzeler, EA, Held, J, Andrews, KT, and Hansen, FK (2018).One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites European Journal of Medicinal Chemistry, 158:801--813.