Molecular Design, Synthesis, and Pharmacology of Novel and Selective Histone Deacetylae 10 (HDAC10) Inhibitors

组蛋白脱乙酰酶(HDAC)是一个由18个表观遗传修饰因子组成的家族，分为4类。组蛋白脱乙酰酶抑制剂(HDACi)是为了纠正由于组蛋白脱乙酰酶活性异常引起的生物过程的失调而开发的。HDAC6和HDAC10属于HDAC家族的IIb类亚组。HDAC10的靶点和生物学功能仍然不明确，也没有发表具有生物活性的特定的HDAC10抑制剂。我们已经合成并表征了第一个HDAC10的特异性抑制剂，我们证明了这些抑制剂可以诱导急性B细胞白血病和淋巴瘤细胞的凋亡。我们的目标是通过基于结构的设计、合成、体外测试以及包括基因敲除策略在内的细胞特性的组合，合理地改进我们的先导化合物。基于使用重组HDAC的体外图谱，可以选择有前途的候选者。我们将在更大的白血病细胞群中测试这种抑制物诱导细胞凋亡的作用。为了全面揭示HDAC10的蛋白质靶点，我们将在全球蛋白质组和转录组分析中使用我们的新HDAC10抑制剂。这将包括对对HDAC10抑制后反应或抵抗凋亡诱导的白血病细胞进行比较分析，我们希望对新的HDAC10靶点进行功能测试。为了进一步发现HDAC10的创新抑制剂，我们将合成并测试针对嵌合体的蛋白水解酶(PROTAC)，这些嵌合体可以抑制HDAC10的催化活性，并进一步降解它。我们新的HDAC10抑制剂是确定HDAC10下游靶点和功能的工具。此外，此类化合物有望成为白血病的新治疗选择。

Histone deacetylases (HDACs) are a family of 18 epigenetic modifiers that fall into 4 classes. Histone deacetylase inhibitors (HDACi) are developed to correct dysregulated biological processes due to aberrant HDAC activities. HDAC6 and HDAC10 belong to the class IIb subgroup of the HDAC family. The targets and biological functions of HDAC10 are still ill-defined and no specific HDAC10 inhibitors with biological activity are published. We have synthesized and characterized the first specific inhibitors of HDAC10 and we demonstrate that these induce apoptosis of acute B cell leukemia and lymphoma cells. We aim to rationally improve our lead compounds by a combination of structure-based design, synthesis, in vitro testing as well as cellular characterization including genetic knockout strategies. Promising candidates can be selected based on the in vitro profiling using recombinant HDACs. We will test such inhibitors against a larger panel of leukemic cells regarding apoptosis induction. To comprehensively reveal the protein targets of HDAC10, we will use our new HDAC10 inhibitors in global proteome and transcriptome analyses. This will include a comparative analysis of leukemic cells that respond or resist apoptosis induction upon HDAC10 inhibition and we want to carry out functionally tests for new HDAC10 targets. To discover further innovative inhibitors of HDAC10, we will synthesize and test proteolysis targeting chimeras (PROTACs) that inhibit the catalytic activity of HDAC10 and additionally degrade it. Our new HDAC10 inhibitors are tools to identify the downstream targets and functions of HDAC10. Moreover, such compounds could prospectively be used as new treatment options for leukemia.