Identification of a Novel Protein Arginine Methyltransferase 5 Inhibitor in Non-small Cell Lung Cancer by Structure-Based Virtual Screening

Abstract

Protein arginine methyltransferase 5 (PRMT5) is able to regulate gene transcription by catalyzing the symmetrical dimethylation of arginine residue of histone, which plays a key role in tumorigenesis. Many efforts have been taken in discovering small-molecular inhibitors against PRMT5, but very few were reported and most of them were SAM-competitive. EPZ015666 is a recently reported PRMT5 inhibitor with a new binding site, which is different from S-adenosylmethionine (SAM)-binding pocket. This new binding site provides a new clue for the design and discovery of potent and specific PRMT5 inhibitors. In this study, the structure-based virtual screening targeting this site was firstly performed to identify potential PRMT5 inhibitors. Then, the bioactivity of the candidate compound was studied. MTT results showed that compound T1551 decreased cell viability of A549 and H460 non-small cell lung cancer cell lines. By inhibiting the methyltransferase activity of PRMT5, T1551 reduced the global level of H4R3 symmetric dimethylation (H4R3me2s). T1551 also downregulated the expression of oncogene FGFR3 and eIF4E, and disturbed the activation of related PI3K/AKT/mTOR and ERK signaling in A549 cell. Finally, we investigated the conformational spaces and identified collective motions important for description of T1551/PRMT5 complex by using molecular dynamics simulation and normal mode analysis methods. This study provides a novel non-SAM-competitive hit compound for developing small molecules targeting PRMT5 in non-small cell lung cancer.

Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA

“…This might also explain why the addition of high doses of EPZ015666 does not further decrease proliferation of T cells cultured at high MTA concentrations. Therefore, the development of more potent and/or MTA-selective PRMT5 inhibitors is necessary and is focus of ongoing studies (49,50). However, we demonstrated that PRMT5 inhibition suppresses human CD8 þ T cells, with the synthetic PRMT5 inhibitor EPZ015666 acting similar to MTA, a naturally occurring PRMT5-inhibiting molecule.…”

Computational study on the selective inhibition mechanism of MS402 to the first and second bromodomains of BRD4

“…The binding free energies of MS402 and BRD4‐BDs were analyzed by the molecular mechanics generalized born surface area method . Herein, a total of 500 snapshots were extracted from the last 50 ns MD trajectory and calculated as follows: Where Δ G MMGBSA denoted the binding free energy between BD and MS402 and could be divided into three terms: molecular mechanical energy (Δ E MM ), solvation energy (Δ G sol ), and entropy (− T Δ S ).…”

“…Finally, 200 ns MD simulations at a temperature The binding free energies of MS402 and BRD4-BDs were analyzed by the molecular mechanics generalized born surface area method. 27,[44][45][46] Herein, a total of 500 snapshots were extracted from the last 50 ns MD trajectory and calculated as follows:…”

Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel

“…Its higher potency derivative, GSK3326595, is currently in clinical trials (20,21). Many other PRMT5is have been developed (21)(22)(23)(24)(25)(26)(27)(28)(29)(30), of which JNJ64619178, PF-06939999, and PRT543, are also in clinical trials (31)(32)(33). Notably, some work through distinct mechanisms from EPZ015666 and GSK3326595, for example JNJ64619178 targets the SAM binding domain (21).…”