Structure based development and biological characterization of selective inhibitors of histone deacetylases (HDACs) 8 and 10.

组蛋白去乙酰化酶是表观遗传基因调控和非组蛋白底物活性的重要调节剂。虽然对于HDAC 1-3和6，已经获得了许多有效的选择性抑制剂，但对于其他亚型，对选择性抑制剂及其抑制的后果知之甚少。在以前的工作中，我们已经确定HDAC 8和10作为有前途的抗癌靶点，并将各自的抑制剂作为进一步优化的候选物。HDAC 8和与抑制剂复合的同系物的晶体结构以及HDAC 10的同源性模型将用于先导结构的结构和基于计算机的优化。在这个项目中，我们将进一步研究HDAC 8和10在癌细胞增殖中的作用，并以体外和细胞培养的有效性和选择性的双导向方式优化可用的先导结构。优化的抑制剂将进行动物研究，以阐明HDAC 8和10用于未来药物开发的潜力。从计算化学到合成，再到生物和临床前药物测试，这三个小组的不同专业知识将促进独特的协同作用，以实现本提案的目标。

Histone deacetylases are important modulators of epigenetic gene regulation and the activity of non-histone protein substrates. While for HDACs 1-3 and 6 many potent selective inhibitors have been obtained, for other subtypes much less is known on selective inhibitors and the consequences of their inhibition. In previous work, we have identified HDACs 8 and 10 as promising anticancer targets and respective inhibitors as candidates for further optimization. Crystal structures of HDAC8 and homologues in complex with inhibitors as well as homology models of HDAC10 will be used for structure- and computer-based optimization of the lead structures. Within this project we will further investigate the role of HDAC8 and 10 in the proliferation of cancer cells and optimize available lead structures in a bioguided fashion for potency and selectivity, both in-vitro and in cell culture. Optimized inhibitors will be subjected to animal studies to clarify the potential of HDAC8 and 10 for future drug development. The different expertise of the three groups from computational chemistry via synthesis to biological and preclinical drug testing will facilitate a unique synergy to achieve the goals of this proposal.