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

Autor:	Mould DP; Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, U.K., Alli C; CRT Discovery Laboratories , Babraham Campus, Babraham, Cambridgeshire CB22 3AT, U.K., Bremberg U; Beactica AB , Uppsala Business Park, Virdings allé 2, 75450, Uppsala, Sweden., Cartic S; CRT Discovery Laboratories , Babraham Campus, Babraham, Cambridgeshire CB22 3AT, U.K., Jordan AM; Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, U.K., Geitmann M; Beactica AB , Uppsala Business Park, Virdings allé 2, 75450, Uppsala, Sweden., Maiques-Diaz A; Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, U.K., McGonagle AE; Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, U.K., Somervaille TCP; Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, U.K., Spencer GJ; Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, U.K., Turlais F; CRT Discovery Laboratories , Babraham Campus, Babraham, Cambridgeshire CB22 3AT, U.K., Ogilvie D; Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX, U.K.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2017 Oct 12; Vol. 60 (19), pp. 7984-7999. Date of Electronic Publication: 2017 Sep 21.
DOI:	10.1021/acs.jmedchem.7b00462
Abstrakt:	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 K d value of 32 nM and an EC 50 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.
Databáze:	MEDLINE
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