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Covalent inhibitors of nicotinamide N-methyltransferase (NNMT) provide evidence for target engagement challenges in situ
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2018-04-10 , DOI: 10.1016/j.bmcl.2018.04.017
Hsin-Yu Lee , Radu M. Suciu , Benjamin D. Horning , Ekaterina V. Vinogradova , Olesya A. Ulanovskaya , Benjamin F. Cravatt

Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of nicotinamide using S-adenosyl-L-methionine (SAM) as a methyl donor and, through doing so, can modulate cellular methylation potential to impact diverse epigenetic processes. NNMT has been implicated in a range of diseases, including cancer and metabolic disorders. Potent, selective, and cell-active inhibitors would constitute valuable probes to study the biological functions and therapeutic potential of NNMT. We previously reported the discovery of electrophilic small molecules that inhibit NNMT by reacting with an active-site cysteine residue in the SAM-binding pocket. Here, we have used activity-based protein profiling (ABPP)-guided medicinal chemistry to optimize the potency and selectivity of NNMT inhibitors, culminating in the discovery of multiple alpha-chloroacetamide (αCA) compounds with sub-µM IC50 values in vitro and excellent proteomic selectivity in cell lysates. However, these compounds showed much weaker inhibition of NNMT in cells, a feature that was not shared by off-targets of the αCAs. Our results show the potential for developing potent and selective covalent inhibitors of NNMT, but also highlight challenges that may be faced in targeting this enzyme in cellular systems.



中文翻译:

烟酰胺N-甲基转移酶(NNMT)的共价抑制剂为原位靶点参与挑战提供了证据

烟酰胺N-甲基转移酶(NNMT)使用S催化烟酰胺的N-甲基化-腺苷-L-蛋氨酸(SAM)作为甲基供体,并且通过这样做,可以调节细胞甲基化的潜力,从而影响各种表观遗传过程。NNMT与多种疾病有关,包括癌症和代谢性疾病。有力的,选择性的和具有细胞活性的抑制剂将构成有价值的探针,以研究NNMT的生物学功能和治疗潜力。我们先前报道了亲电性小分子通过与SAM结合袋中的活性位半胱氨酸残基反应而抑制NNMT的发现。在这里,我们使用了基于活性的蛋白质谱(ABPP)指导的药物化学,以优化NNMT抑制剂的效价和选择性,最终发现了多个亚微米IC 50值的α-氯乙酰胺(αCA)化合物。体外和细胞裂解物中优异的蛋白质组选择性。但是,这些化合物对细胞中NNMT的抑制作用要弱得多,αCAs脱靶点没有共享这一特征。我们的结果显示了开发有效的和选择性的NNMT共价抑制剂的潜力,但也突出了在细胞系统中靶向这种酶可能面临的挑战。

更新日期:2018-04-10
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