Your browser doesn't support javascript.
loading
Novel Bcl-2 Inhibitors Selectively Disrupt the Autophagy-Specific Bcl-2-Beclin 1 Protein-Protein Interaction.
Dong, Xiaonan; Liang, Qiren; Pan, Yun-Zu; Wang, Xiaoyu; Kuo, Yi-Chun; Chiang, Wei-Chung; Zhang, Xuewu; Williams, Noelle S; Rizo, Josep; Levine, Beth; De Brabander, Jef K.
Affiliation
  • Dong X; University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • Liang Q; University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • Pan YZ; University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • Wang X; University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • Kuo YC; University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • Chiang WC; University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • Zhang X; University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • Williams NS; University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • Rizo J; University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • Levine B; University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • De Brabander JK; University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
ACS Med Chem Lett ; 13(9): 1510-1516, 2022 Sep 08.
Article in En | MEDLINE | ID: mdl-36105331
ABSTRACT
Autophagy plays essential roles in a wide variety of physiological processes, such as cellular homeostasis, metabolism, development, differentiation, and immunity. Selective pharmacological modulation of autophagy is considered a valuable potential therapeutic approach to treat diverse human diseases. However, development of such therapies has been greatly impeded by the lack of specific small molecule autophagy modulators. Here, we performed structure-activity relationship studies on a previously discovered weak Bcl-2 inhibitor SW076956, and developed a panel of small molecule compounds that selectively released Bcl-2-mediated inhibition of autophagy-related Beclin 1 compared to apoptosis-related Bax at nanomolar concentration. Our NMR analysis showed that compound 35 directly binds Bcl-2 and specifically inhibits the interaction between the Bcl-2 and Beclin 1 BH3 domains without disruption of the Bcl-2-Bax BH3 interaction. More broadly, this proof-of-concept study demonstrates that targeting protein-protein interactions of the intrinsic autophagy regulatory network can serve as a valuable strategy for the development of autophagy-based therapeutics.

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: ACS Med Chem Lett Year: 2022 Document type: Article Affiliation country: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: ACS Med Chem Lett Year: 2022 Document type: Article Affiliation country: Estados Unidos