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.
Daniel P Mould  1 ,  Cristina Alli  2 ,  Ulf Bremberg  3 ,  Sharon Cartic  2 ,  Allan M Jordan  1 ,  Matthis Geitmann  3 ,  Alba Maiques-Diaz  4 ,  Alison E McGonagle  1 ,  Tim C P Somervaille  4 ,  Gary J Spencer  4 ,  Fabrice Turlais  2 ,  Donald Ogilvie  1
Affiliations
  • 1. Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, U.K.
  • 2. CRT Discovery Laboratories , Babraham Campus, Babraham, Cambridgeshire CB22 3AT, U.K.
  • 3. Beactica AB , Uppsala Business Park, Virdings allé 2, 75450, Uppsala, Sweden.
  • 4. Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, U.K.
PMID: 28892629 DOI: 10.1021/acs.jmedchem.7b00462
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.

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