Structural analogues of PFI-1 varying at the sulfur core were prepared, and their activities as BET inhibitors in myeloid cell lines and primary cells from patients with acute myeloid leukemia were studied. Docking calculations followed by molecular dynamics simulations revealed the binding mode of the newly prepared inhibitors, suggesting explanations for the observed high enantiospecificity of the inhibitory activity.
Imetelstat, a telomerase inhibitor, has shown clinical activity in patients with Myeloproliferative Neoplasms (MPN), including primary myelofibrosis (PMF) and essential thrombocythemia (ET). Imetelstat is an oligonucleotide with a nucleotide sequence that is complementary to and therefore specifically binds with high affinity to the template region of the RNA component of human telomerase and acts as a potent, competitive inhibitor of telomerase enzymatic activity. Although inhibition of telomerase by imetelstat leads to telomere length (TL) shortening, its mechanisms to induce responses in MPN need further elucidation.
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