Biological and Medicinal Chemistry

Development of a First-in-Class Small Molecule Inhibitor of the C-terminal Hsp90 Dimerization

Authors

  • Sanil Bhatia 1. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Lukas Spanier 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • David Bickel 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Niklas Dienstbier 1. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Vitalij Woloschin 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Melina Vogt 1. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Henrik Pols 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Beate Lungerich 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Jens Reiners 3. Center for Structural Studies, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Narges Aghaallaei 4. Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Germany ,
  • Daniela Diedrich 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Benedikt Frieg 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany & 5. John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry) & Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, Jülich, Germany ,
  • Julian Schliehe-Diecks 1. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Bertan Boop 6. Institute for Pharmaceutical and Medicinal Chemistry, PharmaCampus, Westphalian Wilhelms University, Münster, Germany ,
  • Franziska Lang 1. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Mohanraj Gopalswamy 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Jennifer Loschwitz 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Baubak Bajohgli 4. Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Germany ,
  • Julia Skokowa 4. Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Germany ,
  • Arndt Borkhardt 1. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Julia Hauer 7. Department of Pediatrics, Pediatric Hematology and Oncology, University Hospital Carl Gustav Carus, Dresden, Germany & 8. National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany ,
  • Finn K. Hansen 9. Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute University of Bonn, Bonn, Germany ,
  • Sander H.J. Smits 3. Center for Structural Studies, Heinrich Heine University Düsseldorf, Düsseldorf, Germany & 10. Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany ,
  • Joachim Jose 6. Institute for Pharmaceutical and Medicinal Chemistry, PharmaCampus, Westphalian Wilhelms University, Münster, Germany ,
  • Holger Gohlke 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany & 5. John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry) & Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, Jülich, Germany ,
  • Thomas Kurz 2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Abstract

Heat shock protein 90 (Hsp90) is a promising therapeutic target due to its involvement in stabilizing several aberrantly expressed oncoproteins. In cancerous cells, Hsp90 expression is elevated, thereby contributing in exerting anti-apoptotic effects, which is essential for the malignant transformation and progression of several tumor types. Most of the Hsp90 inhibitors (Hsp90i) under investigation target the ATP binding site in the N-terminal domain (NTD) of Hsp90. However, adverse effects, including induction of the pro-survival resistance mechanism (heat shock response or HSR) and associated dose-limiting toxicity, have so far precluded clinical approval of these Hsp90i. In contrast, modulators that interfere with the C-terminal domain (CTD) of Hsp90 do not inflict HSR and, thus, emerge as a promising alternative approach to target Hsp90. Since the CTD dimerization of Hsp90 is essential for its chaperone activity, interfering with this essential dimerization process by small-molecule protein-protein interaction (PPI) inhibitors is a promising strategy for anticancer drug research. We have developed the first-in-class small molecule inhibitor (5b) targeting the Hsp90 CTD dimerization interface, based on a tripyrimidonamide scaffold through structure-based molecular design, chemical synthesis, binding mode model prediction, assessment of the biochemical affinity and efficacy against therapy-resistant leukemia cells. 5b reduces xenotransplantation of leukemia cells in zebrafish models and induces apoptosis in BCR-ABL1+ (T315I) tyrosine kinase inhibitors (TKIs) resistant leukemia cells, without inducing HSR.

Content

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Supplementary material

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Supplementary Note 1 and 2
- See Supplementary Note 1 for Chemical Synthesis (including general methods, synthetic protocols, compound characterization, and spectral data - SI Figure 1 - 20) and supplementary figures (SI Figure 21-31) and supplementary table (SI Table 1-2) - See Supplementary Note 2 for Physicochemical properties of 5b