Development of (4-Cyanophenyl)glycine Derivatives as Reversible Inhibitors of Lysine Specific Demethylase 1

J Med Chem. 2017 Oct 12;60(19):7984-7999. doi: 10.1021/acs.jmedchem.7b00462. Epub 2017 Sep 21.

Abstract

Inhibition of lysine specific demethylase 1 (LSD1) has been shown to induce the differentiation of leukemia stem cells in acute myeloid leukemia (AML). Irreversible inhibitors developed from the nonspecific inhibitor tranylcypromine have entered clinical trials; however, the development of effective reversible inhibitors has proved more challenging. Herein, we describe our efforts to identify reversible inhibitors of LSD1 from a high throughput screen and subsequent in silico modeling approaches. From a single hit (12) validated by biochemical and biophysical assays, we describe our efforts to develop acyclic scaffold-hops from GSK-690 (1). A further scaffold modification to a (4-cyanophenyl)glycinamide (e.g., 29a) led to the development of compound 32, with a Kd value of 32 nM and an EC50 value of 0.67 μM in a surrogate cellular biomarker assay. Moreover, this derivative does not display the same level of hERG liability as observed with 1 and represents a promising lead for further development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Biomarkers
  • Cell Line, Tumor
  • Computer Simulation
  • Drug Design
  • Drug Discovery
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Ether-A-Go-Go Potassium Channels / drug effects
  • Glycine / analogs & derivatives*
  • Glycine / chemical synthesis
  • Glycine / pharmacology
  • High-Throughput Screening Assays
  • Histone Demethylases / antagonists & inhibitors*
  • Humans
  • Leukemia / drug therapy*
  • Models, Molecular
  • Molecular Docking Simulation
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship
  • Tranylcypromine / analogs & derivatives
  • Tranylcypromine / chemistry
  • Tranylcypromine / pharmacology

Substances

  • 4-((2-(2,7-diazaspiro(3.5)nonan-7-yl)-2-oxoethyl)-((3-fluoro-4-methoxyphenyl)methyl)amino)benzonitrile
  • Antineoplastic Agents
  • Biomarkers
  • Enzyme Inhibitors
  • Ether-A-Go-Go Potassium Channels
  • Spiro Compounds
  • Tranylcypromine
  • Histone Demethylases
  • KDM1A protein, human
  • Glycine