Lysine specific demethylase 1 (LSD1) is a histone modifying enzyme that suppresses gene expression through demethylation of lysine 4 on histone H3. The anti-tumor activity of GSK2879552 and GSK-LSD1, ...potent, selective irreversible inactivators of LSD1, has previously been described. Inhibition of LSD1 results in a cytostatic growth inhibitory effect in a range of acute myeloid leukemia cell lines. To enhance the therapeutic potential of LSD1 inhibition in this disease setting, a combination of LSD1 inhibition and all-
retinoic acid was explored. All-
retinoic acid is currently approved for use in acute promyelocytic leukemia in which it promotes differentiation of abnormal blast cells into normal white blood cells. Combined treatment with all-
retinoic acid and GSK2879552 results in synergistic effects on cell proliferation, markers of differentiation, and, most importantly, cytotoxicity. Ultimately the combination potential for LSD1 inhibition and ATRA will require validation in acute myeloid leukemia patients, and clinical studies to assess this are currently underway.
Post-translational modification of the p53 signaling pathway plays an important role in cell cycle progression and stress-induced apoptosis. Indeed, a large body of work has shown that dysregulation ...of p53 and its E3 ligase MDM2 by the ubiquitin-proteasome system (UPS) promotes carcinogenesis and malignant transformation. Thus, drug discovery efforts have focused on the restoration of wild-type p53 activity or inactivation of oncogenic mutant p53 by targeted inhibition of UPS components, particularly key deubiquitinases (DUBs) of the ubiquitin-specific protease (USP) class. However, development of selective small-molecule USP inhibitors has been challenging, partly due to the highly conserved structural features of the catalytic sites across the class. To tackle this problem, we devised a protein engineering strategy for rational design of inhibitors for DUBs and other UPS proteins. We employed a phage-displayed ubiquitin variant (UbV) library to develop inhibitors targeting the DUBs USP7 and USP10, which are involved in regulating levels of p53 and MDM2. We were able to identify UbVs that bound USP7 or USP10 with high affinity and inhibited deubiquitination activity. We solved the crystal structure of UbV.7.2 and rationalized the molecular basis for enhanced affinity and specificity for USP7. Finally, cell death was increased significantly by UbV.7.2 expression in a colon cancer cell line that was treated with the chemotherapy drug cisplatin, demonstrating the therapeutic potential of inhibiting USP7 by this approach.
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•Potent and selective inhibitors were developed for USP7 and USP10.•Crystal structure of UbV.7.2 sheds light on binding and inhibition mechanism.•UbV.7.2 destabilizes MDM2 and stabilizes p53.•UbV.10.1 affects p53 localization and induces p53 degradation.•UbV.7.2 enhances DNA-damage-induced cancer cell death.
Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for targeted therapies. The current report describes the ...discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inactivator of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes, suggesting this may be used as a predictive biomarker of activity.
•LSD1 is important in oncogenesis, suggesting it may serve as a therapeutic target•GSK2879552 is a potent, selective, oral, mechanism-based inactivator of LSD1•GSK2879552 has an antitumor effect in SCLC cells in vitro and in vivo•DNA hypomethylation of a signature probe set predicts sensitivity to GSK2879552
Mohammad et al. identify the orally available lysine demethylase 1 (LSD1)-selective inhibitor GSK2879552 and find unexpectedly that some small cell lung cancer cell lines are sensitive to LSD1 inhibition. Mohammad et al. further identify a potential biomarker predictive of response to GSK2879552.
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