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

  • Mol Cancer Ther. 2018 Jun;17(6):1177-1186. doi: 10.1158/1535-7163.MCT-17-1209.
Andrea Local   #  1 ,  Hongying Zhang   #  1 ,  Khalid D Benbatoul  1 ,  Peter Folger  1 ,  Xia Sheng  1 ,  Cheng-Yu Tsai  2 ,  Stephen B Howell  2 ,  William G Rice  3
Affiliations
  • 1. Aptose Biosciences Inc., San Diego, California.
  • 2. Moores Cancer Center and Department of Medicine, University of California, San Diego, California.
  • 3. Aptose Biosciences Inc., San Diego, California. [email protected].
  • # Contributed equally.
PMID: 29626127 DOI: 10.1158/1535-7163.MCT-17-1209
Abstract

APTO-253 is a phase I clinical stage small molecule that selectively induces CDKN1A (p21), promotes G0-G1 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)3]. FRET assays demonstrated that both monomeric APTO-253 and Fe(253)3 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)3 and APTO-253 on G-quadruplex DNA motifs. Mol Cancer Ther; 17(6); 1177-86. ©2018 AACR.

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