ArticleCell chemical biology2022
A campaign targeting a conserved Hsp70 binding site uncovers how subcellular localization is linked to distinct biological activities.
Article in Cell chemical biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- Development of domain-specific probes ofAntimicrobial agents and chemotherapy · 2026Article
- Emerging magic bullet: subcellular organelle-targeted cancer therapy.Medical review (2021) · 2025Review
- Proteostasis perturbation of N-Myc leveraging HSP70 mediated protein turnover improves treatment of neuroendocrine prostate cancer.Nature communications · 2024Article
- J-domain proteins: From molecular mechanisms to diseases.Cell stress & chaperones · 2024Article
- Non-Essential Amino Acid Availability Influences Proteostasis and Breast Cancer Cell Survival During Proteotoxic Stress.Molecular cancer research : MCR · 2023Article
- Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models.Pharmacological research · 2023Article
- Editorial: The role of mortalin in biology and disease.Frontiers in cell and developmental biology · 2023Article
- Maximizing CRISPRi efficacy and accessibility with dual-sgRNA libraries and optimal effectors.eLife · 2022Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
The potential of small molecules to localize within subcellular compartments is rarely explored. To probe this question, we measured the localization of Hsp70 inhibitors using fluorescence microscopy. We found that even closely related analogs had dramatically different distributions, with some residing predominantly in the mitochondria and others in the ER. CRISPRi screens supported this idea, showing that different compounds had distinct chemogenetic interactions with Hsp70s of the ER (HSPA5/BiP) and mitochondria (HSPA9/mortalin) and their co-chaperones. Moreover, localization seemed to determine function, even for molecules with conserved binding sites. Compounds with distinct partitioning have distinct anti-proliferative activity in breast cancer cells compared with anti-viral activity in cellular models of Dengue virus replication, likely because different sets of Hsp70s are required in these processes. These findings highlight the contributions of subcellular partitioning and chemogenetic interactions to small molecule activity, features that are rarely explored during medicinal chemistry campaigns.
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Registered trials
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