Exploration and Biological Evaluation of Basic Heteromonocyclic Propanamide Derivatives as SARDs for the Treatment of Enzalutamide-Resistant Prostate Cancer
| Autor: | Michael L. Mohler, Ramesh Narayanan, Duane D. Miller, Dong Jin Hwang, Yali He, Thirumagal Thiyagarajan, Suriyan Ponnusamy |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.drug_class Antineoplastic Agents Antiandrogen Article Rats Sprague-Dawley Mice Structure-Activity Relationship Prostate cancer chemistry.chemical_compound Prostate Nitriles Phenylthiohydantoin Drug Discovery LNCaP Androgen Receptor Antagonists medicine Animals Humans Enzalutamide Cell Proliferation Dose-Response Relationship Drug Molecular Structure Prostatic Neoplasms Neoplasms Experimental medicine.disease Amides Propanamide Rats Androgen receptor HEK293 Cells medicine.anatomical_structure chemistry Drug Resistance Neoplasm Receptors Androgen Benzamides Cancer research Molecular Medicine Drug Screening Assays Antitumor Pharmacophore |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00439 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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