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 (IC 50 = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15u (IC 50 = 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 the lymphoma cell line Raji with the IC 50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15u induced expression of CD86 and CD11b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation. The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazole-fused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1A inhibitors.

Discovery of [1,2,3]triazolo[4,5-d]pyrimidine derivatives as highly potent, selective, and cellularly active USP28 inhibitors

“…The synthetic route of the title compounds is demonstrated in Scheme 1 . The starting chlorides 1 were prepared from 4,6-dihydroxy-2-mercaptopyrimidine within 6 steps according to the previously reported methods 14 , 15 , 16 . And the target compounds 3 – 24 were readily prepared in 70%–90% yields by reacting 1 with different amines 2 under alkaline conditions.…”

“…Additionally, based on previously reported LSD1 inhibitors and co-crystal structures, we proposed the ‘2 + 1’ model for the development of new LSD1 inhibitors, highlighting the heterocycles bearing an amine group as a class of emerging scaffolds targeting LSD1 19 , 20 . Based on this proposed model, we have successfully designed different types of LSD1 inhibitors that meet with this model 15 , 21 , 22 , 23 . Considering that the title compounds also featured the heterocyclic scaffold equipped with an amine group, we evaluated the inhibitory activity against LSD1, but found that compound 19 was inactive against LSD1 (IC 50 > 100 μmol/L, Table 2 ).…”

1,2,3-Triazole Nucleus as a Versatile Tool for the Obtainment of Novel Biologically Active Compounds: an Overview

“…Dificultando ainda mais, em geral, menos de 0,01 % dos protótipos de compostos bioativos sintetizados nos laboratórios têm sucesso nas etapas préclínicas, que compreendem os ensaios biológicos in vitro realizados após a etapa de síntese, purificação e caracterização. [1][2][3][4][5] Dentro deste contexto, sintetizar compostos contendo um núcleo 1,2,3-triazólico em sua estrutura molecular (1-13) é uma estratégia eficiente e amplamente explorada [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] para obtenção de novas moléculas com variadas atividades biológicas, como: antiviral [26][27][28][29] , antídoto 30,31 , antiinflamatória 32 , antibacteriana 33 , antitumoral 34,35 e antimicrobiana 36 (Figura 2). Dentre as vantagens de se incorporar este heterociclo, de origem estritamente sintética, na estrutura molecular do produto planejado destacam-se: (i) podem interagir com diferentes receptores biológicos através de ligações de hidrogênio e/ou interações hidrofóbicas do tipo π-stacking com resíduos de aminoácidos como a fenilalanina; (ii) podem atuar como elos de união entre duas moléculas (linkers), possibilitando a obtenção de compostos híbridos; (iii) podem ser introduzidos na estrutura molecular de um composto como um bioisóstero, por exemplo, na substituição de uma função amida, a fim de evitar reações de hidrólise.…”

Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

“…CDK4, one of the main controllers of cell cycle entry, is substantially overexpressed in glioblastoma, breast and ovarian cancers, making it an attractive therapeutic target 27 , 28 , 29 . Some recent efforts have generated promising leads by targeting compounds to allosteric binding sites in CDKs 30 , 31 , 32 , 33 . The allosteric pocket varies among CDKs, in contrast to the highly conserved ATP-binding site.…”