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Structure-Activity Relationship Study of Tris-Benzamides as Estrogen Receptor Coregulator Binding Modulators.
Lee, Tae-Kyung; Kassees, Kara; Chen, Chia-Yuan; Viswanadhapalli, Suryavathi; Parra, Karla; Vadlamudi, Ratna K; Ahn, Jung-Mo.
Afiliação
  • Lee TK; Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas 75080, United States.
  • Kassees K; Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas 75080, United States.
  • Chen CY; Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas 75080, United States.
  • Viswanadhapalli S; Department of Obstetrics and Gynecology, University of Texas Health, San Antonio, Texas 78229, United States.
  • Parra K; Departments of Urology and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • Vadlamudi RK; Department of Obstetrics and Gynecology, University of Texas Health, San Antonio, Texas 78229, United States.
  • Ahn JM; Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas 75080, United States.
ACS Pharmacol Transl Sci ; 7(7): 2023-2043, 2024 Jul 12.
Article em En | MEDLINE | ID: mdl-39022350
ABSTRACT
Estrogen receptor coregulator binding modulators (ERXs) are a novel class of molecules targeting the interaction between estrogen receptor α (ERα) and its coregulator proteins, which has proven to be an attractive strategy for overcoming endocrine resistance in breast cancer. We previously reported ERX-11, an orally bioavailable tris-benzamide, that demonstrated promising antitumor activity against ERα-positive breast cancer cells. To comprehend the significance of the substituents in ERX-11, we carried out structure-activity relationship studies. In addition, we introduced additional alkyl substituents at either the N- or C-terminus to improve binding affinity and biological activity. Further optimization guided by conformational restriction led to the identification of a trans-4-phenylcyclcohexyl group at the C-terminus (18h), resulting in a greater than 10-fold increase in binding affinity and cell growth inhibition potency compared to ERX-11. Tris-benzamide 18h disrupted the ERα-coregulator interaction and inhibited the ERα-mediated transcriptional activity. It demonstrated strong antiproliferative activity on ERα-positive breast cancer cells both in vitro and in vivo, offering a promising potential as a therapeutic candidate for treating ERα-positive breast cancer.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article