Zhai Shiyang, Honin Irina, Schäker-Hübner Linda, Hanl Maria, Jacobi Lukas, Dressler Finn, Pieńkowska Dominika Ewa, König Philipp, Gerhartz Jan, Voget Rabea, Bendas Gerd, Gütschow Michael, Meissner Felix, Burckhardt Bjoern B, Nowak Radosław P, Steinebach Christian, Hansen Finn K
Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.
Institute of Innate Immunity, Department of Systems Immunology and Proteomics, Medical Faculty, University of Bonn, 53127 Bonn, Germany.
J Med Chem. 2025 Jul 10;68(13):13793-13821. doi: 10.1021/acs.jmedchem.5c00674. Epub 2025 Jun 18.
Proteolysis-targeting chimeras (PROTACs) are emerging new therapeutic modalities that facilitate the targeted degradation of disease-relevant proteins via an event-driven mode of action. In this work, we report the design, synthesis, and biological evaluation of the first-in-class selective degraders of the class IIb histone deacetylases (HDACs) 6 and 10. To this end, the dual HDAC6/10 inhibitor tubastatin A and a ring-opened analog were connected via well-established PROTAC linkers to pomalidomide and phenylglutarimides as cereblon recruiters. This approach led to the discovery of (HDAC6 DC = 13 nM; HDAC10 DC = 29 nM) as a potent degrader of class IIb HDACs. Importantly, neither degraded HDAC1/8 (class I) and HDAC4/7 (class IIa), nor induced histone H3 hyperacetylation, thereby confirming its selectivity for class IIb HDACs. Due to its low cytotoxicity against hematological and solid cancer cell lines, represents a valuable tool compound for the chemical knockdown of class IIb HDACs.
蛋白酶靶向嵌合体（PROTACs）是新兴的治疗方式，通过事件驱动的作用模式促进疾病相关蛋白的靶向降解。在这项工作中，我们报道了首个二类组蛋白去乙酰化酶（HDACs）6和10的选择性降解剂的设计、合成及生物学评价。为此，通过成熟的PROTAC接头将双HDAC6/10抑制剂tubastatin A和一个开环类似物与泊马度胺和作为脑啡肽募集剂的苯基戊二酰亚胺连接。这种方法导致发现了（HDAC6降解常数=13 nM；HDAC10降解常数=29 nM）作为二类HDACs的有效降解剂。重要的是，既不降解HDAC1/8（一类）和HDAC4/7（二类a），也不诱导组蛋白H3高乙酰化，从而证实了其对二类HDACs的选择性。由于其对血液学和实体癌细胞系的低细胞毒性，代表了用于化学敲低二类HDACs的有价值的工具化合物。
