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Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity
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SYSNO ASEP 0510407 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity Author(s) Wu, H. (US)
Yang, K. (US)
Zhang, Z. (US)
Leisten, E.D. (US)
Li, Z. (US)
Xie, H. (US)
Liu, J. (US)
Smith, K. A. (US)
Nováková, Zora (BTO-N) ORCID, RID
Bařinka, Cyril (BTO-N) RID, ORCID
Tang, W. (US)Number of authors 11 Source Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 62, č. 15 (2019), s. 7042-7057Number of pages 16 s. Language eng - English Country US - United States Keywords INDUCED PROTEIN-DEGRADATION ; E3 UBIQUITIN LIGASE ; MULTIPLE-MYELOMA Subject RIV FR - Pharmacology ; Medidal Chemistry OECD category Pharmacology and pharmacy R&D Projects GA15-19640S GA ČR - Czech Science Foundation (CSF) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support BTO-N - RVO:86652036 UT WOS 000480500600015 EID SCOPUS 85071340946 DOI 10.1021/acs.jmedchem.9b00516 Annotation 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. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2020 Electronic address https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00516
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