APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells

APTO-253 is a phase I clinical stage small molecule that selectively induces CDKN1A (p21), promotes G(0)-G(1) cell-cycle arrest, and triggers apoptosis in acute myeloid leukemia (AML) cells without producing myelosuppression in various animal species and humans. Differential gene expression analysis identified a pharmacodynamic effect on MYC expression, as well as induction of DNA repair and stress response pathways. APTO253 was found to elicit a concentration-and time-dependent reduction in MYC mRNA expression and protein levels. Gene ontogeny and structural informatic analyses suggested a mechanism involving G-quadruplex (G(4)) stabilization. Intracellular pharmacokinetic studies in AML cells revealed that APTO-253 is converted intracellularly from a monomer to a ferrous complex [Fe(253)(3)]. FRET assays demonstrated that both monomeric APTO-253 and Fe(253)(3) stabilize G(4) structures from telomeres, MYC, and KIT promoters but do not bind to non-G(4) doublestranded DNA. Although APTO-253 exerts a host of mechanistic sequelae, the effect of APTO-253 on MYC expression and its downstream target genes, on cell-cycle arrest, DNA damage, and stress responses can be explained by the action of Fe(253)(3) and APTO-253 on G-quadruplex DNA motifs. (C) 2018 AACR.