Development of (4-cyanophenyl) glycine derivatives as reversible inhibitors of lysine specific demethylase 1.
AuthorsMould, Daniel P
Jordan, Allan M
Somervaille, Tim C P
Spencer, Gary J
Ogilvie, Donald J
AffiliationDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester , Wilmslow Road, Manchester, M20 4BX
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AbstractInhibition 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.
CitationDevelopment of (4-cyanophenyl) glycine derivatives as reversible inhibitors of lysine specific demethylase 1. 2017, 60 (19):7984-7999 J Med Chem
JournalJournal of Medicinal Chemistry