Rapid Two-Step Multicomponent Synthesis and Structure-degradation Relationships of Selective HDAC6 PROTAC Degraders

  • J Med Chem. 2026 Sep 10;69(17):21018-21043. doi: 10.1021/acs.jmedchem.6c02045.
Mikhail Tsymliakov  1 ,  Maria Hanl  1 ,  Jana Enns  2 ,  Shiyang Zhai  1 ,  Eleonora Ferretti  2 ,  Philipp König  1 ,  Rama Kousa  1 ,  Jia-Wey Tu  3 ,  Christian Steinebach  4  5 ,  Michael Gütschow  4 ,  Gerd Bendas  1 ,  Sanil Bhatia  3 ,  Günther Weindl  2 ,  Finn K Hansen  1
Affiliations
  • 1. Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121Bonn, Germany.
  • 2. Department of Pharmacology and Toxicology, Pharmaceutical Institute, University of Bonn, Gerhard-Domagk-Str. 3, 53121Bonn, Germany.
  • 3. Department of Paediatric Oncology, Haematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Dusseldorf, Moorenstr. 5, 40225Düsseldorf, Germany.
  • 4. Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121Bonn, Germany.
  • 5. Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Straße 17, 17489Greifswald, Germany.
PMID: 42720482 DOI: 10.1021/acs.jmedchem.6c02045
Abstract

This work reports on the development of selective histone deacetylase 6 (HDAC6) degraders based on a peptoid scaffold. Structure-based design identified the isocyanide-derived cap region as suitable exit vector for linker attachment, enabling rapid generation of CRBN-recruiting PROTACs via the Ugi four-component reaction. A focused library of 12 degraders revealed a strong dependence of activity on linker composition, with octyl-linked compounds (9e-h) showing the strongest HDAC6 degradation with half-maximal degradation values of 17-36 nM in kinetic HDAC6 degradation assays. The lead compounds selectively degraded HDAC6 in MM.1S and MV4-11 cells without affecting class I HDACs and demonstrated clean proteomic profiles. Functionally, compounds 9e and 9f displayed submicromolar antiproliferative activity against FLT3-ITD-mutated Acute Myeloid Leukemia cells and suppressed proinflammatory signaling in immune cells. Both effects were associated in part with residual class I HDAC inhibition. Overall, this study establishes an efficient multicomponent strategy for PROTAC Synthesis and highlights key structure-degradation relationships.

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