Concomitant inhibition of multiple oncogenic pathways is a desirable goal in cancer therapy. To achieve such an outcome with a single molecule would simplify treatment regimes. Herein the core features of ruxolitinib (1), a marketed JAK1/2 inhibitor, have been merged with the HDAC inhibitor vorinostat (2), leading to new molecules that are bispecific targeted JAK/HDAC inhibitors. A preferred pyrazole substituted pyrrolopyrimidine, 24, inhibits JAK1 and HDACs 1, 2, 3, 6, and 10 with IC₅₀ values of less than 20 nM, is <100 nM potent against JAK2 and HDAC11, and is selective for the JAK family against a panel of 97 kinases. Broad cellular antiproliferative potency of 24 is supported by demonstration of JAK-STAT and HDAC pathway blockade in hematological cell lines. Methyl analogue 45 has an even more selective profile. This study provides new leads for assessment of JAK and HDAC pathway dual inhibiton achieved with a single molecule.

中文翻译：

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基于鲁索替尼和伏立诺他的配体有效的Janus激酶（JAK）和组蛋白脱乙酰基酶（HDAC）双重抑制剂的合成

同时抑制多种致癌途径是癌症治疗中的理想目标。用单个分子实现这样的结果将简化治疗方案。本文将市售JAK1 / 2抑制剂ruxolitinib（1）的核心特征与HDAC抑制剂伏立诺他（vorinostat）（2）合并，从而产生了新的分子，它们是双特异性靶向JAK / HDAC抑制剂。优选的吡唑取代的吡咯并嘧啶24抑制JAK1，HDAC 1、2、3、6和10的IC ₅₀值小于20 nM，对JAK2和HDAC11的效价<100 nM，并且对JAK家族具有选择性一组97种激酶。广泛的细胞抗增殖能力为24血液细胞系中的JAK-STAT和HDAC信号通路阻滞实验证明了这一点。甲基类似物45具有更高的选择性。这项研究为评估用单个分子实现的JAK和HDAC途径双重抑制提供了新的线索。