As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a K_d value of 22 nM and a biochemical IC₅₀ of 57 nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping as a method to develop structurally diverse, potent inhibitors of LSD1.

作为我们开发LSD1可逆抑制剂的持续努力的一部分，我们鉴定了一系列4-（吡咯烷-3-基）苄腈衍生物，可作为文献抑制剂GSK-690的成功骨架。活性最高的化合物21g的K _d值为22 nM，生化IC ₅₀为57 nM。此外，与GSK-690相比，该化合物在hERG离子通道上显示出更高的选择性，并且对相关的酶MAO-A和B没有活性。在人THP-1急性髓细胞白血病细胞中，21g有人发现其被发现可以增加替代细胞生物标志物CD86的表达。这项工作进一步证明了脚手架跳跃作为开发结构多样，有效的LSD1抑制剂的方法的多功能性。