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Development of (4-cyanophenyl) glycine derivatives as reversible inhibitors of lysine specific demethylase 1.
Mould, Daniel P Alli, C Bremberg, U Cartic, S Jordan, Allan M Geitmann, M Maiques-Diaz, Alba McGonagle, A Somervaille, Tim C P Spencer, Gary J
Mould, Daniel P
Alli, C
Bremberg, U
Cartic, S
Jordan, Allan M
Geitmann, M
Maiques-Diaz, Alba
McGonagle, A
Somervaille, Tim C P
Spencer, Gary J
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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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2017-10-12
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Development of (4-cyanophenyl) glycine derivatives as reversible inhibitors of lysine specific demethylase 1. 2017, 60 (19):7984-7999 J Med Chem