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Design and synthesis of triple inhibitors of janus kinase (JAK), histone deacetylase (HDAC) and Heat Shock Protein 90 (HSP90)
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2018-03-03 , DOI: 10.1016/j.bmcl.2018.03.009
Lianbin Yao 1 , Sten Ohlson 2 , Brian W Dymock 1
Affiliation  

Inhibition of multiple signaling pathways in a cancer cell with a single molecule could result in better therapies that are simpler to administer. Efficacy may be achieved with reduced potency against individual targets if there is synergy through multiple pathway inhibition. To achieve this, it is necessary to be able to build multi-component ligands by joining together key pharmacophores in a way which maintains sufficient activity against the individual pathways. In this work, designed triple inhibiting ligands are explored aiming to block three completely different target types: a kinase (JAK2), an epigenetic target (HDAC) and a chaperone (HSP90). Although these enzymes have totally different functions they are related through inter-dependent pathways in the developing cancer cell. Synthesis of several complex multi-inhibiting ligands are presented along with initial enzyme inhibition data against 3 biological target classes of interest. A lead compound, 47, was discovered which had low micromolar activity for all 3 targets. Further development of these complex trispecific designed multiple ligands could result in a ‘transient drug’, an alternative combination therapy for treating cancer mediated via a single molecule.



中文翻译:

janus激酶(JAK)、组蛋白去乙酰化酶(HDAC)和热休克蛋白90(HSP90)三重抑制剂的设计与合成

用单个分子抑制癌细胞中的多个信号通路可能会产生更好的治疗方法,并且更易于给药。如果通过多途径抑制产生协同作用,则可能会降低针对单个目标的效力来实现疗效。为了实现这一点,有必要通过将关键药效团连接在一起来构建多组分配体,以保持对各个途径的足够活性。在这项工作中,探索了设计的三重抑制配体,旨在阻断三种完全不同的靶标类型:激酶 (JAK2)、表观遗传靶标 (HDAC) 和分子伴侣 (HSP90)。尽管这些酶具有完全不同的功能,但它们在发育中的癌细胞中通过相互依赖的途径相关联。介绍了几种复杂的多重抑制配体的合成以及针对 3 个感兴趣的生物目标类别的初始酶抑制数据。一种先导化合物,47,被发现对所有 3 个目标都具有低微摩尔活性。这些复杂的三特异性设计的多个配体的进一步开发可能会产生一种“瞬态药物”,一种用于治疗通过单个分子介导的癌症的替代联合疗法。

更新日期:2018-03-03
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