FluorinatedN,N-Dialkylaminostilbenes Repress Colon Cancer by Targeting MethionineS-Adenosyltransferase 2A

Abstract

Methionine S-adenosyltransferase 2A (MAT2A) is the catalytic subunit for synthesis of S-adenosylmethionine (SAM), the principal methyl donor in many biological processes. MAT2A is up-regulated in many cancers, including liver cancer and colorectal cancer (CRC) and is a potentially important drug target. We developed a family of fluorinated N,N-dialkylaminostilbene agents, called FIDAS agents, that inhibit the proliferation of CRC cells in vitro and in vivo. Using a biotinylated FIDAS analog, we identified the catalytic subunit of MAT2A as the direct and exclusive binding target of these FIDAS agents. MAT2B, an associated regulatory subunit of MAT2A, binds indirectly to FIDAS agents through its association with MAT2A. FIDAS agents inhibited MAT2A activity in SAM synthesis, and depletion of MAT2A by shRNAs inhibited CRC cell growth. A novel FIDAS agent delivered orally repressed CRC xenografts in athymic nude mice. These findings suggest that FIDAS analogs targeting MAT2A represent a family of novel and potentially useful agents for cancer treatment.

Phenylethynyl-substituted heterocycles inhibit cyclin D1 and induce the expression of cyclin-dependent kinase inhibitor p21Wif1/Cip1in colorectal cancer cells

“…As desired, these stilbene-based agents did not affect methionine S-adenosyltransferase-1 (MAT1) 16–19 that served as the principal source of SAM necessary for other cellular needs. Unlike a recent report 20 of other MAT2A inhibitors, we also demonstrated in vivo potency in a xenograft model using colorectal cancer cells 12 .…”

“…Computational modeling studies provided guidance with respect to synthetic design but required experimental confirmation. Prior modeling work and pull-down assays confirmed MAT2A as the sole target of stilbene analogs 12 , but it was important to confirm experimentally that the acetylene analogs, such as phenylethynyl-substituted heterocycles 5 , shared the same target as these stilbene analogs. In support of the binding of phenylethynyl-substituted heterocycles 5 to MAT2A, we synthesized and utilized a biologically active, D-(+)-biotin derivative 6 (Fig.…”

“…The diarylacetylenes 2 also possessed the desired property of having minimal effects on the cardiac potassium hERG channel 14, 15 . Molecular docking studies suggested that diphenylacetylenes, like their stilbene counterparts 12 , targeted the catalytic subunit (MAT2A) of MAT2 23 .…”

Peptide Inhibitors Targeting the Neisseria gonorrhoeae Pivotal Anaerobic Respiration Factor AniA

“…The pose ensemble was filtered to reject poses that did not have sufficient shape complementarity with the active site of the protein. In separate docking runs, the binding poses of the ligand structure were refined by MD simulations followed by free energy calculations using the Sander module from the Amber12 package (91) as previously described (92)(93)(94)(95). The AniA-peptide binding complex was neutralized by adding appropriate counterions and was solvated in a rectangular box of TIP3P (transferable intermolecular potential with 3-points model) water molecules with a minimum solute wall distance of 10 Å (96).…”

Application of Mannich bases to the synthesis of hydroxymethylated isoflavonoids as potential antineoplastic agents

“…Our past experience along these same lines in developing inhibitors that affect Wnt signaling encouraged these efforts. 10,11 …”