Exploration of 5-cyano-6-phenylpyrimidin derivatives containing an 1,2,3-triazole moiety as potent FAD-based LSD1 inhibitors

Abstract

Histone lysine specific demethylase 1 (LSD1) has become a potential therapeutic target for the treatment of cancer. Discovery and develop novel and potent LSD1 inhibitors is a challenge, although several of them have already entered into clinical trials. Herein, for the first time, we reported the discovery of a series of 5-cyano-6-phenylpyrimidine derivatives as LSD1 inhibitors using flavin adenine dinucleotide (FAD) similarity-based designing strategy, of which compound 14q was finally identified to repress LSD1 with IC 50 = 183 nmol/L. Docking analysis suggested that compound 14q fitted well into the FAD-binding pocket. Further mechanism studies showed that compound 14q may inhibit LSD1 activity competitively by occupying the FAD binding sites of LSD1 and inhibit cell migration and invasion by reversing epithelial to mesenchymal transition (EMT). Overall, these findings showed that compound 14q is a suitable candidate for further development of novel FAD similarity-based LSD1 inhibitors.

Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1

“…In 2020, our group reported a series of 5-cyano-6phenyl pyrimidine analogues containing the 1,2,3-triazole moiety to be FAD competitive LSD1 inhibitors (Figure 5B). 57 SARs studies identified compound 32 as the most potent candidate (IC 50 = 183 nM). Compound 32 was shown to inhibit LSD1 reversibly and time-dependently.…”

Tranylcypromine Based Lysine-Specific Demethylase 1 Inhibitor: Summary and Perspective

“…In comparison with irreversible LSD1 inhibitors, noncovalent reversible LSD1 inhibitors present potential advantages in phenotype and safety, and they are grouped into two categories: non-natural ones and natural products. In recent years, many research groups, including us, − have designed and synthesized numerous noncovalent reversible LSD1 inhibitors with reduced toxicity, potent preclinical antileukemic effects, and sub-micromolar potencies, including dithiocarbamates, aminothiazole triazoles, pyrimidines, and triazole-fused pyridines. For instance, in 2019, our group identified of a series of triazole-fused pyrimidine derivatives as highly potent LSD1 inhibitors, of which the most potent compound (IC 50 = 49 nM) inhibited LSD1 reversibly and was highly selective to LSD1 over MAO-A and -B.…”

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

“…The Lamarckian genetic algorithm was used for the conformational search of the inhibitor within the docking box size. During docking process, 100 independent runs were performed and the resulting poses were clustered using a root-mean-square deviation (RMSD) cutoff of 1 Å ( Ma et al, 2020 ; Wu et al, 2020 ). The docking pose with the lowest energy in the largest cluster was visually analyzed and then selected for the following MD simulations.…”