PUBLICATION
Rational Design of Allosteric and Selective Inhibitors of the Molecular Chaperone TRAP1
- Authors
- Sanchez-Martin, C., Moroni, E., Ferraro, M., Laquatra, C., Cannino, G., Masgras, I., Negro, A., Quadrelli, P., Rasola, A., Colombo, G.
- ID
- ZDB-PUB-200423-8
- Date
- 2020
- Source
- Cell Reports 31: 107531 (Journal)
- Registered Authors
- Keywords
- HSP90, TRAP1, allosteric ligands, anticancer compound, cancer cells, chaperone inhibitors, mitochondria, mitochondrial biology, molecular dynamics, neurofibroma, zebrafish
- MeSH Terms
-
- Allosteric Regulation
- Animals
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology
- Drug Design
- Female
- HSP90 Heat-Shock Proteins/antagonists & inhibitors*
- HSP90 Heat-Shock Proteins/chemistry
- HSP90 Heat-Shock Proteins/genetics
- HSP90 Heat-Shock Proteins/metabolism
- Humans
- Male
- Mice
- Molecular Chaperones/antagonists & inhibitors*
- Molecular Chaperones/chemistry
- Molecular Chaperones/genetics
- Molecular Chaperones/metabolism
- Molecular Dynamics Simulation
- Nerve Sheath Neoplasms/drug therapy
- Recombinant Proteins/chemistry
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Small Molecule Libraries/chemistry*
- Small Molecule Libraries/pharmacology*
- Zebrafish
- PubMed
- 32320652 Full text @ Cell Rep.
Citation
Sanchez-Martin, C., Moroni, E., Ferraro, M., Laquatra, C., Cannino, G., Masgras, I., Negro, A., Quadrelli, P., Rasola, A., Colombo, G. (2020) Rational Design of Allosteric and Selective Inhibitors of the Molecular Chaperone TRAP1. Cell Reports. 31:107531.
Abstract
TRAP1 is the mitochondrial paralog of the heat shock protein 90 (HSP90) chaperone family. Its activity as an energy metabolism regulator has important implications in cancer, neurodegeneration, and ischemia. Selective inhibitors of TRAP1 could inform on its mechanisms of action and set the stage for targeted drug development, but their identification was hampered by the similarity among active sites in HSP90 homologs. We use a dynamics-based approach to identify a TRAP1 allosteric pocket distal to its active site that can host drug-like molecules, and we select small molecules with optimal stereochemical features to target the pocket. These leads inhibit TRAP1, but not HSP90, ATPase activity and revert TRAP1-dependent downregulation of succinate dehydrogenase activity in cancer cells and in zebrafish larvae. TRAP1 inhibitors are not toxic per se, but they abolish tumorigenic growth of neoplastic cells. Our results indicate that exploiting conformational dynamics can expand the chemical space of chaperone antagonists to TRAP1-specific inhibitors with wide therapeutic opportunities.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping