Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1

Autor: Ulf Bremberg, Donald J. Ogilvie, Matthis Geitmann, Gary J. Spencer, Allan M. Jordan, Alison E. McGonagle, Daniel P. Mould, Tim C. P. Somervaille
Rok vydání: 2017
Předmět:
0301 basic medicine
Pyrrolidines
Cancer therapy
Reversible inhibitor
Cellular differentiation
Clinical Biochemistry
LSD1
Pharmaceutical Science
Biochemistry
chemistry.chemical_compound
0302 clinical medicine
Drug Discovery
Enzyme Inhibitors
Histone Demethylases
chemistry.chemical_classification
Manchester Cancer Research Centre
biology
Stereoisomerism
Molecular Docking Simulation
030220 oncology & carcinogenesis
Molecular Medicine
Epigenetics
Selectivity
Stereochemistry
hERG
Acute myeloid leukaemia
Inhibitory Concentration 50
Structure-Activity Relationship
03 medical and health sciences
Cell Line
Tumor
Nitriles
Humans
Molecular Biology
IC50
Ion channel
Binding Sites
Epigenetic therapy
ResearchInstitutes_Networks_Beacons/mcrc
Organic Chemistry
KDM1A
Protein Structure
Tertiary
Enzyme Activation
Benzonitrile
030104 developmental biology
Enzyme
Stem cell differentiation
chemistry
Drug Design
biology.protein
Zdroj: Mould, D, Bremberg, U, Jordan, A, Geitmann, M, Mcgonagle, A, Somervaille, T, Spencer, G & Ogilvie, D 2017, ' Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1 ', Bioorganic and Medicinal Chemistry Letters, vol. 27, no. 20, pp. 4755-4759 . https://doi.org/10.1016/j.bmcl.2017.08.052
ISSN: 0960-894X
DOI: 10.1016/j.bmcl.2017.08.052
Popis: As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22 nM and a biochemical IC50 of 57 nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping as a method to develop structurally diverse, potent inhibitors of LSD1.
Databáze: OpenAIRE
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