Dataset Information

Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation.

ABSTRACT: Survivin, a homodimeric member of the Inhibitor of Apoptosis Protein (IAP) family, is required for cancer cell survival and overexpressed in almost all solid tumors. However, targeting survivin has been challenging due to its "undruggable" nature. Recently, we used a novel approach to target the dimerization interface and identified inhibitors of two scaffolds that can directly bind to and inhibit survivin dimerization. One of the scaffolds, represented by the compound LQZ-7, contains an undesirable labile hydrazone linker and a potentially nonfunctional furazanopyrazine ring that we attempted to eliminate in this study. We found one compound, 7I, that is more active than the parent compound, LQZ-7, and when given orally effectively inhibits xenograft tumor growth and induces survivin loss in tumors. These findings indicate that 7I with a stable linker and a quinoxaline ring can be used as a lead for further optimization of this novel class of survivin inhibitors.

SUBMITTER: Peery R

PROVIDER: S-EPMC8216492 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation.

Peery Robert R Kyei-Baffour Kwaku K Dong Zizheng Z Liu Jianguo J de Andrade Horn Pedro P Dai Mingji M Liu Jing-Yuan JY Zhang Jian-Ting JT

Journal of medicinal chemistry 20200609 13

Survivin, a homodimeric member of the Inhibitor of Apoptosis Protein (IAP) family, is required for cancer cell survival and overexpressed in almost all solid tumors. However, targeting survivin has been challenging due to its "undruggable" nature. Recently, we used a novel approach to target the dimerization interface and identified inhibitors of two scaffolds that can directly bind to and inhibit survivin dimerization. One of the scaffolds, represented by the compound LQZ-7, contains an undesir ...[more]

PMID: 32421328

Similar Datasets

Project description:All eukaryotes rely on selective proteolysis to control the abundance of key regulatory proteins and maintain a healthy and properly functioning proteome. Most of this turnover is catalyzed by the 26S proteasome, an intricate, multi-subunit proteolytic machine. Proteasomes recognize and degrade proteins first marked with one or more chains of poly-ubiquitin, the addition of which is actuated by hundreds of ligases that individually identify appropriate substrates for ubiquitylation. Subsequent proteasomal digestion is essential and influences a myriad of cellular processes in species as diverse as plants, fungi and humans. Importantly, dysfunction of 26S proteasomes is associated with numerous human pathologies and profoundly impacts crop performance, thus making an understanding of proteasome dynamics critically relevant to almost all facets of human health and nutrition. Given this widespread significance, it is not surprising that sophisticated mechanisms have evolved to tightly regulate 26S proteasome assembly, abundance and activity in response to demand, organismal development and stress. These include controls on transcription and chaperone-mediated assembly, influences on proteasome localization and activity by an assortment of binding proteins and post-translational modifications, and ultimately the removal of excess or damaged particles via autophagy. Intriguingly, the autophagic clearance of damaged 26S proteasomes first involves their modification with ubiquitin, thus connecting ubiquitylation and autophagy as key regulatory events in proteasome quality control. This turnover is also influenced by two distinct biomolecular condensates that coalesce in the cytoplasm, one attracting damaged proteasomes for autophagy, and the other reversibly storing proteasomes during carbon starvation to protect them from autophagic clearance. In this review, we describe the current state of knowledge regarding the dynamic regulation of 26S proteasomes at all stages of their life cycle, illustrating how protein degradation through this proteolytic machine is tightly controlled to ensure optimal growth, development and longevity.

Dataset Information

Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation.

Publications

Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets