Exploration and Biological Evaluation of Basic Heteromonocyclic Propanamide Derivatives as SARDs for the Treatment of Enzalutamide-Resistant Prostate Cancer.
Yali HeDong-Jin HwangSuriyan PonnusamyThirumagal ThiyagarajanMichael L MohlerRamesh NarayananDuane D MillerPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- prostate cancer
- radical prostatectomy
- induced apoptosis
- wild type
- cell cycle arrest
- molecular dynamics
- atrial fibrillation
- molecular docking
- genome wide
- high resolution
- high throughput
- randomized controlled trial
- gene expression
- signaling pathway
- endoplasmic reticulum stress
- benign prostatic hyperplasia
- tissue engineering
- hiv testing
- dna binding
- young adults
- cell death
- oxide nanoparticles
- childhood cancer