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

Abstract

APTO-253 is a phase I clinical stage small molecule that selectively induces CDKN1A (p21), promotes G-G 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. APTO-253 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 (G4) stabilization. Intracellular pharmacokinetic studies in AML cells revealed that APTO-253 is converted intracellularly from a monomer to a ferrous complex [Fe(253)]. FRET assays demonstrated that both monomeric APTO-253 and Fe(253) stabilize G4 structures from telomeres, MYC, and KIT promoters but do not bind to non-G4 double-stranded 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) and APTO-253 on G-quadruplex DNA motifs. .

Polyamine synthesis as a target of MYC oncogenes

“…resolved for transcription to occur. Compounds like enniantin-B, TH3, and APTO-253 that stabilize this structure decrease MYC transcription (44,45). Furthermore, efficient MYC gene transcription needs docking of BRD proteins and other co-activating molecules, including IKZF, NME2, and CDK9 at the promoter.…”

NMR Studies of G-Quadruplex Structures and G-Quadruplex-Interactive Compounds

“…For example, TMPyP4, a G-quadruplex-interactive compound developed through structure-based rational drug design [13], and Telomestatin, one of the most potent G-quadruplex stabilizing compounds [14], have been shown to inhibit human telomerase. Several other G-quadruplex-interactive compounds have been shown to inhibit expression of oncogenes, including MYC [15] and BCL-2 [16].…”

Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

“…In the setting of disease, MTF1 could contribute to tumor metastasis and chemoresistance in some cancer cells (52). a MTF1 inhibitor (35), is a small molecule with antitumor activity against a wide range of human malignancies in in vitro and in xenograft mouse models (53,54). In the present study, APTO-253 demonstrated inhibitory activity on the expression of pathogenic molecules (IL-6, CCL5) from RASFs exposed to synergistic cytokines and antiarthritic activity in a CIA model.…”