Abstract
A series of propanamide derivatives were designed, synthesized, and pharmacologically characterized as selective androgen receptor degraders (SARDs) and pan-antagonists that exert a broad-scope androgen receptor (AR) antagonism. Incorporating different basic heteromonocyclic B-ring structural elements in the common A-ring-linkage-B-ring nonsteroidal antiandrogen general pharmacophore contributed to a novel scaffold of small molecules with SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-69 (11), UT-155 (12), and UT-34 (13). Compound 26f exhibited inhibitory and degradation effects in vitro in a wide array of wtAR, point mutant, and truncation mutant-driven prostate cancers (PCs). Further, 26f inhibited tumor cell growth in a xenograft model composed of enzalutamide-resistant (EnzR) LNCaP cells. These results demonstrate an advancement toward the development of novel SARDs and pan-antagonists with efficacy against EnzR prostate cancers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / chemical synthesis
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Amides / chemistry
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Amides / pharmacology*
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Androgen Receptor Antagonists / chemical synthesis
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Androgen Receptor Antagonists / chemistry
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Androgen Receptor Antagonists / pharmacology*
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Benzamides / pharmacology
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / drug effects*
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Drug Screening Assays, Antitumor
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HEK293 Cells
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Humans
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Male
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Mice
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Molecular Structure
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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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Nitriles / pharmacology
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Phenylthiohydantoin / pharmacology
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Rats
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Rats, Sprague-Dawley
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Receptors, Androgen / metabolism*
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Structure-Activity Relationship
Substances
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Amides
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Androgen Receptor Antagonists
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Antineoplastic Agents
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Benzamides
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Nitriles
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Receptors, Androgen
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Phenylthiohydantoin
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enzalutamide