高活化的Janus激酶（JAK）信号在人类癌症中是一个受欢迎的药物靶点。许多突变的JAK分子以及先天性和获得性耐药机制限制了JAK抑制剂（JAKi）的疗效。越来越多的证据表明，表观遗传机制控制JAK依赖信号级联。就像JAK一样，组蛋白去乙酰化酶（HDAC）家族的表观遗传修饰因子调节细胞的生长和发育，并且在癌细胞中常常失调。抑制组蛋白去乙酰化酶（HDACi）消除致癌的JAK依赖信号级联的概念揭示了JAK和HDAC之间错综复杂的相互作用。在这里，我们总结如何结构不同，广泛作用以及同工酶特异性的HDACi，混合融合药效团包含JAKi和HDACi，以及针对JAKs的蛋白酶解靶向嵌合体取代四个JAK蛋白JAK1、JAK2、JAK3和酪氨酸激酶-2。这些药物通过特定的转录依赖过程和机制，抑制异常的JAK活性，并改变JAK的磷酸化和稳定性。药理学上抑制HDACs消除了JAK的变构激活，克服了竞争ATP的第一和第二类型的JAKi的限制，并与JAKi有良好的相互作用。由于这些发现是在培养的细胞，实验动物和癌症患者中获得的，因此我们压缩了临床前和转化相关性。我们还讨论了未来关于调节JAKs的乙酰化依赖性机制的研究如何允许合理设计改进癌症患者的治疗。重要性声明：可逆的赖氨酸-ɛ-N乙酰化和脱乙酰化循环控制磷酸化依赖的Janus激酶-信号转导子和转录活化子信号。这些基本分子机制之间的错综复杂的相互作用提供了使用现代小分子抑制剂的药理干预策略的机会。这可以帮助患有癌症的患者。版权所有©2023年美国药理学和实验疗法学会。

Hyperactivated Janus kinase (JAK) signaling is an appreciated drug target in human cancers. Numerous mutant JAK molecules as well as inherent and acquired drug resistance mechanisms limit the efficacy of JAK inhibitors (JAKi). There is accumulating evidence that epigenetic mechanisms control JAK-dependent signaling cascades. Like JAKs, epigenetic modifiers of the histone deacetylase (HDAC) family regulate the growth and development of cells and are often dysregulated in cancer cells. The notion that inhibitors of histone deacetylases (HDACi) abrogate oncogenic JAK-dependent signaling cascades illustrates an intricate crosstalk between JAKs and HDACs. Here, we summarize how structurally divergent, broad-acting as well as isoenzyme-specific HDACi, hybrid fusion pharmacophores containing JAKi and HDACi, and proteolysis targeting chimeras for JAKs inactivate the four JAK proteins JAK1, JAK2, JAK3, and tyrosine kinase-2. These agents suppress aberrant JAK activity through specific transcription-dependent processes and mechanisms that alter the phosphorylation and stability of JAKs. Pharmacological inhibition of HDACs abrogates allosteric activation of JAKs, overcomes limitations of ATP-competitive type 1 and type 2 JAKi, and interacts favorably with JAKi. Since such findings were collected in cultured cells, experimental animals, and cancer patients, we condense preclinical and translational relevance. We also discuss how future research on acetylation-dependent mechanisms that regulate JAKs might allow the rational design of improved treatments for cancer patients. SIGNIFICANCE STATEMENT: Reversible lysine-ɛ-N acetylation and deacetylation cycles control phosphorylation-dependent Janus kinase-signal transducer and activator of transcription signaling. The intricate crosstalk between these fundamental molecular mechanisms provides opportunities for pharmacological intervention strategies with modern small molecule inhibitors. This could help patients suffering from cancer.Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.