Optimization\nand Biological Evaluation of Novel 1<i>H</i>‑Pyrrolo[2,3‑<i>c</i>]pyridin Derivatives\nas Potent and Reversible Lysine Specific Demethylase 1 Inhibitors\nfor the Treatment of Acute Myelogenous Leukemia

Lysine-specific demethylase 1 (LSD1) plays a vital role\nin the\nepigenetic regulation of various cancers, making it a promising therapeutic\ntarget for anticancer treatments. Herein, we designed and synthesized\na novel series of 1<i>H</i>-pyrrolo[2,3-<i>c</i>]pyridin derivatives as potent LSD1 inhibitors. A detailed structure–activity\nrelationship exploration was carried out to discover multiple derivatives\nwith nanomolar enzymatic IC<sub>50</sub> values. Further biological\nevaluation demonstrated that these compounds acted as selective and\nreversible LSD1 inhibitors. The representative compounds exhibited\nhighly potent antiproliferative activity against both AML (MV4–11\nand Kasumi-1) and SCLC (NCI-H526) cell lines. Additionally, they effectively\nactivated CD86 mRNA expression in MV4–11 cells and induced\ndifferentiation of AML cell lines. Notably, the most promising compound <b>23e</b> showed a favorable oral PK profile and effectively suppressed\nthe tumor growth in an AML xenograft model. Overall, our medicinal\nchemistry efforts provide compound <b>23e</b> as a lead compound\nfor developing LSD1 inhibitors for the treatment of AML and other\nadvanced malignancies.