The role of chlorine atom on the binding between acrylonitrile derivatives and fat mass and obesity‐associated protein

Abstract

In this work, seven acrylonitrile derivatives were selected as potential inhibitors of fat and obesity‐related proteins (FTO) by the aid of fluorescence spectroscopy, ultraviolet visible spectroscopy, molecular docking, and cytotoxicity methods. Results show that the interaction between 3‐amino‐2‐(4‐chlorophenyl)‐3‐phenylacrylonitrile (1a) and FTO was the strongest among these derivatives. Thermodynamic analysis and molecular modeling show that the main force between 1a and FTO is hydrophobic interaction. The cytotoxicity test showed that the IC50 value of 1a was 46.64 μmol/L, which indicated 1a had the smallest IC50 value and had the best inhibitory effect on the proliferation of leukemia K562 cells among the seven derivatives. Both our previous results and this work show that chlorine atoms play important role in the binding of small molecules and FTO. This work brings new information for the study of FTO inhibitors.

Physio-pathological effects of N6-methyladenosine and its therapeutic implications in leukemia

“…CS1 and CS2 Attenuate LSC self-renewal, reprogram immune response by reducing LILRB4, sensitize leukemia cells to T-cell cytotoxicity, and show potent anti-leukemic efficacy in mouse models [136] acrylonitrile derivative 1a Binding FTO with chlorine atom, inhibits proliferation of leukemia cells [137] Saikosaponin D Inhibites AML cells proliferation, induce apoptosis and cell cycle arrest both in vitro and vivo, particularly in TKIs-resistant cells [138] let-7b-5p mimic Downregulate the expression of FTO and upregulate c-MYC level in AML line cells [139] ALKBH5 inhibitor Compound 1 and 2 Bioactive peptide Reduces leukemia cell viability inhibit AML cell proliferation and promote apoptosis in vitro, and reduce tumor growth in vivo [143,144] the clinical potentials of m6A regulators as diagnostic biomarkers and therapeutic targets. However, the underlying rationales still remain unclear and the clinical applications require further investigations.…”

“…Recently, Bai et al have screened several acrylonitrile derivatives as potential FTO inhibitors. And they found that chlorine atom was involved in the binding between these small molecules and FTO [ 137 ]. Saikosaponin D is identified as an FTO-targeted drug to impair AML cells proliferation, inducing apoptosis and cell cycle arrest both in vitro and vivo, particularly in TKIs-resistant cells [ 138 ].…”

“… [ 133 ] Meclofenamic acid (MA) Competes with FTO binding for the m6A-containing RNA, increase m6A levels [ 134 ] MA2 Binds FTO active surface, induces m6A methylation, inhibits glioblastoma progression in mice [ 135 ] FB23-2 Reduces expression of c-Myc and CEBPA and promotes RARA and ASB2, represses leukemia cell proliferation, survival, and leukemia progression in mice [ 136 ] R-2HG Induces degradation of c-Myc and CEBPA, promotes leukemia cell apoptosis, and inhibits leukemia growth in mice. [ 108 ] CS1 and CS2 Attenuate LSC self-renewal, reprogram immune response by reducing LILRB4, sensitize leukemia cells to T-cell cytotoxicity, and show potent anti-leukemic efficacy in mouse models [ 136 ] acrylonitrile derivative 1a Binding FTO with chlorine atom, inhibits proliferation of leukemia cells [ 137 ] Saikosaponin D Inhibites AML cells proliferation, induce apoptosis and cell cycle arrest both in vitro and vivo, particularly in TKIs-resistant cells [ 138 ] let-7b-5p mimic Downregulate the expression of FTO and upregulate c-MYC level in AML line cells [ 139 ] ALKBH5 inhibitor Compound 1 and 2 Bioactive peptide Reduces leukemia cell viability inhibit AML cell proliferation and promote apoptosis in vitro, and reduce tumor growth in vivo [ 143 , 144 ] …”