Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase 1 (LSD1/KDM1A).

ABSTRACT: Histone lysine specific demethylase 1 (LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8a (IC₅₀ = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15u (IC₅₀ = 49 nmol/L, and K _i = 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3K4me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency of compound 15u. Compound 15u also showed strong antiproliferative activity against four leukemia cell lines (OCL-AML3, K562, THP-1 and U937) as well as

SUBMITTER: Li Z 

PROVIDER: S-EPMC6663923 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature