Elsevier, Bioorganic and Medicinal Chemistry, 2(22), p. 834-841, 2014
DOI: 10.1016/j.bmc.2013.12.006
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The 3′ end formation of mammalian pre-mRNA contributes to gene expression regulation by setting the downstream boundary of the 3′ untranslated region, which in many genes carries regulatory sequences. A large number of protein cleavage factors participate in this pre-mRNA processing step, but chemical tools to manipulate this process are lacking. Guided by a hypothesis that a PPM1 family phosphatase negatively regulates the 3′ cleavage reaction, we have found a variety of new small molecule activators of the in vitro reconstituted pre-mRNA 3′ cleavage reaction. New activators include a cyclic peptide PPM1D inhibitor, a dipeptide with modifications common to histone tails, abscisic acid and an improved L-arginine β-naphthylamide analog. The minimal concentration required for in vitro cleavage has been improved from 200 μM to the 200 nM-100 μM range. These compounds provide unexpected leads in the search for small molecule tools able to affect pre-mRNA 3′ end formation.