Abstract
Lysine specific demethylase 1 (LSD1) and HDAC6 are epigenetic proteins associated with several diseases, including cancer and combined inhibition of these proteins could be highly beneficial in treating some cancers such as AML, MM and solid tumors. Multiple myeloma (MM) is a challenging cancer with fast relapse rate where novel treatment options are the need of the hour. We have designed and developed novel, LSD1 and HDAC6 selective dual inhibitors to target MM. Our dual inhibitor compound 1 shows superior potency in multiple MM cell lines. In MM.1S xenograft model compound 1 shows superior efficacy compared to single agent LSD1 and HDAC6 inhibitors by oral administration and is well tolerated. Further evaluation of the molecule in other cancers is in progress.
Keywords:
Drugs (IMiDs).; Histone deacetylase 6 (HDAC6), Multiple; Lysine-specific demethylase 1 (LSD1); Myeloma (MM), Immunomodulatory imide.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Histone Deacetylase 6 / antagonists & inhibitors*
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Histone Deacetylase 6 / metabolism
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Histone Demethylases / antagonists & inhibitors*
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Histone Demethylases / metabolism
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Humans
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Mice
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Molecular Structure
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Histone Demethylases
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KDM1A protein, human
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HDAC6 protein, human
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Histone Deacetylase 6