Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity

0510407 - BTÚ 2020 RIV US eng J - Journal Article
Wu, H. - Yang, K. - Zhang, Z. - Leisten, E.D. - Li, Z. - Xie, H. - Liu, J. - Smith, K. A. - Nováková, Zora - Bařinka, Cyril - Tang, W.
Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity.
Journal of Medicinal Chemistry. Roč. 62, č. 15 (2019), s. 7042-7057. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR GA15-19640S; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:86652036
Keywords : INDUCED PROTEIN-DEGRADATION * E3 UBIQUITIN LIGASE * MULTIPLE-MYELOMA
OECD category: Pharmacology and pharmacy
Impact factor: 6.205, year: 2019
Method of publishing: Open access
https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00516

Histone deacetylase 6 (HDAC6) primarily catalyzes the removal of acetyl group from the side chain of acetylated lysine residues in cytoplasmic proteins such as a-tubulin and HSP90. HDAC6 is involved in multiple disease-relevant pathways. Based on the proteolysis targeting chimera strategy, we previously developed the first HDAC6 degrader by tethering a pan-HDAC inhibitor with cereblon (CRBN) E3 ubiquitin ligase ligand. We herein report our new generation of multifunctional HDAC6 degraders by tethering selective HDAC6 inhibitor Nexturastat A with CRBN ligand that can synergize with HDAC6 degradation for the antiproliferation of multiple myeloma (MM). This new class of degraders exhibited improved potency and selectivity for the degradation of HDAC6. After the optimization of the linker length and linking positions, we discovered potent HDAC6 degraders with nanomolar DC50 and promising antiproliferation activity in multiple myeloma (MM) cells.
Permanent Link: http://hdl.handle.net/11104/0300924