Design, Synthesis, and Evaluation of New Selective NM23-H2 Binders as c-MYC Transcription Inhibitors via Disruption of the NM23-H2/G-Quadruplex Interaction

J Med Chem. 2017 Aug 24;60(16):6924-6941. doi: 10.1021/acs.jmedchem.7b00421. Epub 2017 Aug 4.

Abstract

c-MYC is one of the important human proto-oncogenes, and transcriptional factor NM23-H2 can activate c-MYC transcription by recognizing the G-quadruplex in the promoter of the gene. Small molecules that inhibit c-MYC transcription by disrupting the NM23-H2/G-quadruplex interaction might be a promising strategy for developing selective anticancer agents. In recent studies, we developed a series of isaindigotone derivatives, which can bind to G-quadruplex and NM23-H2, thus down-regulating c-MYC ( J. Med. Chem. 2017 , 60 , 1292 - 1308 ). Herein, a series of novel isaindigotone derivatives were designed, synthesized, and screened for NM23-H2 selective binding ligands. Among them, compound 37 showed a high specific binding affinity to NM23-H2, effectively disrupting the interaction of NM23-H2 with G-quadruplex, and it strongly down-regulated c-MYC transcription. Furthermore, 37 induced cell cycle arrest and apoptosis, and it exhibited good tumor growth inhibition in a mouse xenograft model. This work provides a new strategy to modulate c-MYC transcription for the development of selective anticancer drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Down-Regulation
  • Doxorubicin / pharmacology
  • Drug Design
  • G-Quadruplexes*
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Ligands
  • Mice, Inbred BALB C
  • Molecular Docking Simulation
  • NM23 Nucleoside Diphosphate Kinases / antagonists & inhibitors*
  • NM23 Nucleoside Diphosphate Kinases / chemistry
  • NM23 Nucleoside Diphosphate Kinases / genetics
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / genetics
  • Pyrroles / administration & dosage
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Quinazolines / administration & dosage
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Quinazolinones / administration & dosage
  • Quinazolinones / chemical synthesis
  • Quinazolinones / chemistry
  • Quinazolinones / pharmacology*
  • Structure-Activity Relationship
  • Transcription, Genetic
  • Xenograft Model Antitumor Assays

Substances

  • 3-(4-(benzyloxy)-2-hydroxybenzylidene)-6-((3-(dimethylamino)propyl)amino)-7-fluoro-2,3-dihydropyrrolo(2,1-b)quinazolin-9(1H)-one
  • Antineoplastic Agents
  • Ligands
  • MYC protein, human
  • NM23 Nucleoside Diphosphate Kinases
  • Proto-Oncogene Proteins c-myc
  • Pyrroles
  • Quinazolines
  • Quinazolinones
  • Doxorubicin
  • NME2 protein, human