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

• Published in: Molecular cancer therapeutics 2018-06, Vol.17 (6), p.1177-1186
• Main Authors: Local, Andrea, Zhang, Hongying, Benbatoul, Khalid D, Folger, Peter, Sheng, Xia, Tsai, Cheng-Yu, Howell, Stephen B, Rice, William G
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Animal species; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cancer; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Cellular stress response; Complications; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; DNA repair; Dose-Response Relationship, Drug; Fluorescence resonance energy transfer; G-Quadruplexes - drug effects; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Imidazoles - pharmacology; Iron; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Molecular chains; Myc protein; Myeloid leukemia; Myelosuppression; Ontogeny; Pharmacodynamics; Pharmacology; Phenanthrolines - pharmacology; Proteins; Proto-Oncogene Proteins c-myc - chemistry; Proto-Oncogene Proteins c-myc - genetics; Signal Transduction - drug effects; Stress, Physiological - drug effects; Telomeres; Time dependence
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-17-1209

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. .