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

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

Author information

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.

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.

PMID:
28892629
DOI:
10.1021/acs.jmedchem.7b00462
[Indexed for MEDLINE]

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