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• W2897350933 abstract "In this issue of Cell Chemical Biology, Park et al., 2018Park S.-H. Baek K.-H. Shin I. Shin I. Subcellular Hsp70 inhibitors promote cancer cell death via different mechanisms.Cell Chem Biol. 2018; 25 (this issue): 1242-1254Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar demonstrate that targeting apoptazole, an Hsp70 inhibitor, to mitochondria induces apoptosis by a distinct mechanism of action different from unmodified apoptazole, which accumulates in the lysosome. These results highlight the power of subcellular localization in small-molecule selectivity. In this issue of Cell Chemical Biology, Park et al., 2018Park S.-H. Baek K.-H. Shin I. Shin I. Subcellular Hsp70 inhibitors promote cancer cell death via different mechanisms.Cell Chem Biol. 2018; 25 (this issue): 1242-1254Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar demonstrate that targeting apoptazole, an Hsp70 inhibitor, to mitochondria induces apoptosis by a distinct mechanism of action different from unmodified apoptazole, which accumulates in the lysosome. These results highlight the power of subcellular localization in small-molecule selectivity. Although phenotypic screening can be a very powerful way to discover small molecules with novel cellular activities, a major challenge is determining the mechanism of action (MoA) for prioritized compounds. This challenge is particularly notable in cancer small-molecule discovery, where cell death and apoptosis are frequently the endpoints under study. It is often assumed that a small molecule has a single MoA to affect a single phenotype. In this issue, however, Park et al., 2018Park S.-H. Baek K.-H. Shin I. Shin I. Subcellular Hsp70 inhibitors promote cancer cell death via different mechanisms.Cell Chem Biol. 2018; 25 (this issue): 1242-1254Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar challenge that notion by showing that a single small-molecule Hsp70 inhibitor can cause apoptosis by distinct MoA, depending on where in the cell the compound is localized. The Hsp70 protein family consists of a number of highly conserved members with various functions that aid in the cellular response to stress. The family members each contain a nucleotide-binding domain with ATPase activity and a substrate-binding domain that undergoes conformational change in response to ATP hydrolysis (Daugaard et al., 2007Daugaard M. Rohde M. Jäättelä M. The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions.FEBS Lett. 2007; 581: 3702-3710Crossref PubMed Scopus (867) Google Scholar, Evans et al., 2010Evans C.G. Chang L. Gestwicki J.E. Heat shock protein 70 (hsp70) as an emerging drug target.J. Med. Chem. 2010; 53: 4585-4602Crossref PubMed Scopus (323) Google Scholar). In mammalian cells, the Hsp70 family proteins differ in their subcellular localization and function: constitutively expressed Hsc70 and inducible Hsp70 are the major cytoplasmic Hsp70s, GRP78 is localized to the endoplasmic reticulum, and mortalin is found in the mitochondria (Daugaard et al., 2007Daugaard M. Rohde M. Jäättelä M. The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions.FEBS Lett. 2007; 581: 3702-3710Crossref PubMed Scopus (867) Google Scholar, Evans et al., 2010Evans C.G. Chang L. Gestwicki J.E. Heat shock protein 70 (hsp70) as an emerging drug target.J. Med. Chem. 2010; 53: 4585-4602Crossref PubMed Scopus (323) Google Scholar). In addition to their well-characterized roles as protein chaperones, Hsp70 proteins have an anti-apoptotic function through their interaction with APAF-1 and AIF-1 (Evans et al., 2010Evans C.G. Chang L. Gestwicki J.E. Heat shock protein 70 (hsp70) as an emerging drug target.J. Med. Chem. 2010; 53: 4585-4602Crossref PubMed Scopus (323) Google Scholar). It has long been known that Hsp70 is upregulated in a wide range of cancers, and high Hsp70 expression is associated with a poor prognosis (Evans et al., 2010Evans C.G. Chang L. Gestwicki J.E. Heat shock protein 70 (hsp70) as an emerging drug target.J. Med. Chem. 2010; 53: 4585-4602Crossref PubMed Scopus (323) Google Scholar). Interestingly, there is evidence supporting the idea that cancer cells are “addicted” to Hsp70 activity, suggesting that the inhibition of Hsp70 activity in tumors would have a beneficial therapeutic effect (Evans et al., 2010Evans C.G. Chang L. Gestwicki J.E. Heat shock protein 70 (hsp70) as an emerging drug target.J. Med. Chem. 2010; 53: 4585-4602Crossref PubMed Scopus (323) Google Scholar). The allure of Hsp70 as a therapeutic target in cancer has led to the development of a number of small molecules that directly target Hsp70 activity. Recent work by Park and colleagues characterized the activity of one such Hsp70 inhibitor, apoptazole (Az) (Park et al., 2018Park S.-H. Baek K.-H. Shin I. Shin I. Subcellular Hsp70 inhibitors promote cancer cell death via different mechanisms.Cell Chem Biol. 2018; 25 (this issue): 1242-1254Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). Their previous efforts demonstrated that Az is a selective inhibitor of Hsp70 and not Hsp60 or Hsp90 (Ko et al., 2015Ko S.-K. Kim J. Na D.C. Park S. Park S.-H. Hyun J.Y. Baek K.-H. Kim N.D. Kim N.-K. Park Y.N. et al.A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities.Chem. Biol. 2015; 22: 391-403Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). They also showed that Az binds to the nucleotide-binding domain of Hsp70 and inhibits its ATPase activity. This inhibition of Hsp70 led to caspase-mediated apoptosis in cancer cells in vitro and, importantly, Az abrogated tumor growth in mouse xenografts (Ko et al., 2015Ko S.-K. Kim J. Na D.C. Park S. Park S.-H. Hyun J.Y. Baek K.-H. Kim N.D. Kim N.-K. Park Y.N. et al.A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities.Chem. Biol. 2015; 22: 391-403Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). In this issue, Park and colleagues provide a more detailed characterization of Az’s MoA (Park et al., 2018Park S.-H. Baek K.-H. Shin I. Shin I. Subcellular Hsp70 inhibitors promote cancer cell death via different mechanisms.Cell Chem Biol. 2018; 25 (this issue): 1242-1254Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). Here, they take advantage of the differential subcellular localization of Hsp70 family members, where they induce apoptosis in cancer cells via distinct mechanisms. In contrast to Hsc70, which is primarily cytosolic, inducible Hsp70 is often found in the lysosomes of cancer cells, where it contributes to lysosomal stability (Kirkegaard et al., 2010Kirkegaard T. Roth A.G. Petersen N.H.T. Mahalka A.K. Olsen O.D. Moilanen I. Zylicz A. Knudsen J. Sandhoff K. Arenz C. et al.Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology.Nature. 2010; 463: 549-553Crossref PubMed Scopus (368) Google Scholar). The authors observed that, upon treatment of cells with Az, the compound was internalized to the lysosome. This lysosomal accumulation of Az resulted in specific inhibition of lysosomal Hsp70, without affecting the activity of cytosolic Hsp70, and led to the induction of lysosomal membrane permeabilization (LMP). Following LMP, cathepsins were released into the cytosol, resulting in mitochondrial cytochrome c release and, ultimately, caspase-mediated apoptosis (Figure 1). In order to further take advantage of the subcellular localization of Hsp70 family members, the authors modified Az with a mitochondrial-targeting triphenylphosphine (TPP) moiety to create Az-TPP-O3. Mortalin, the mitochondria-localized member of the Hsp70 family, had previously been shown to interact with p53 and p66Shc to suppress mitochondrial outer membrane permeabilization (MOMP) and mitochondrial transmembrane pore formation, respectively (Lu et al., 2011Lu W.-J. Lee N.P. Kaul S.C. Lan F. Poon R.T.P. Wadhwa R. Luk J.M. Mortalin-p53 interaction in cancer cells is stress dependent and constitutes a selective target for cancer therapy.Cell Death Differ. 2011; 18: 1046-1056Crossref PubMed Scopus (130) Google Scholar, Orsini et al., 2004Orsini F. Migliaccio E. Moroni M. Contursi C. Raker V.A. Piccini D. Martin-Padura I. Pelliccia G. Trinei M. Bono M. et al.The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential.J. Biol. Chem. 2004; 279: 25689-25695Crossref PubMed Scopus (241) Google Scholar). Mortalin is therefore an attractive target for inducing apoptosis. The authors confirmed that the addition of TPP to Az resulted in mitochondrial localization of Az-TPP-O3, in contrast to the lysosomal localization of the unmodified Az compound. Targeting Az-TPP-O3 to the mitochondria resulted in more potent induction of apoptosis than Az, despite similar inhibitory effects on the ATPase domain of Hsp70. Further studies revealed that treatment of cells with Az-TPP-O3 blocks the interaction of mortalin with p53, leading to MOMP, release of cytochrome C, and apoptosis (Figure 1). Importantly, because Az-TPP-O3 is efficiently localized to the mitochondria, it neither disrupted lysosomal membranes nor impaired autophagy. This work demonstrates two ways in which taking subcellular localization into account could be useful in designing therapeutics. First, targeting a compound to a specific organelle may help to prevent side effects, by limiting the opportunities for a small molecule to interact with unintended targets. Here, the authors observed that, due to its lysosomal localization, Az inhibits the cancer-associated inducible Hsp70 in the lysosome, rather than constitutively expressed Hsc70 that is found in the cytosol. Additionally, targeting Az-TPP-O3 to the mitochondria allowed for the specific inhibition of mortalin, with no effect on either lysosomal or cytosolic Hsp70. Second, targeting to a specific organelle could enhance potency, by enhancing the local concentration of the small molecule. For example, the mitochondrial localization of Az-TPP-O3 increased the apoptotic potency relative to Az, despite the two compounds having a similar IC50 for Hsp70 ATPase activity. Taken together, the findings in this study (Park et al., 2018Park S.-H. Baek K.-H. Shin I. Shin I. Subcellular Hsp70 inhibitors promote cancer cell death via different mechanisms.Cell Chem Biol. 2018; 25 (this issue): 1242-1254Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar) are a reminder that it is not enough to simply get a small molecule to enter a cell; rather, we should also consider where the small molecule goes once it crosses the plasma membrane. Thoughtful approaches to targeting specific organelles could enhance efforts to develop therapeutics for a number of disorders that have a root cause in a particular organelle. For example, increasing evidence for the role of mitochondrial dysfunction in cardiovascular disease suggests that directly targeting the mitochondria could be a potentially valuable approach (Bonora et al., 2018Bonora M. Wieckowski M.R. Sinclair D.A. Kroemer G. Pinton P. Galluzzi L. Targeting mitochondria for cardiovascular disorders: therapeutic potential and obstacles.Nat. Rev. Cardiol. 2018; (Published online September 3, 2018)https://doi.org/10.1038/s41569-018-0074-0Crossref PubMed Scopus (130) Google Scholar). Likewise, targeting small molecules to the lysosome for treatment of lysosomal storage disorders, or targeting the endoplasmic reticulum in Alzheimer’s disease or diabetes, could potentially contribute to the development of novel therapeutics by targeting a truly disease-relevant cellular context (Chadwick et al., 2012Chadwick W. Mitchell N. Martin B. Maudsley S. Therapeutic targeting of the endoplasmic reticulum in Alzheimer’s disease.Curr. Alzheimer Res. 2012; 9: 110-119Crossref PubMed Scopus (27) Google Scholar, Eizirik and Cnop, 2010Eizirik D.L. Cnop M. ER stress in pancreatic beta cells: the thin red line between adaptation and failure.Sci. Signal. 2010; 3 (pe7–pe7)Crossref PubMed Scopus (116) Google Scholar). Subcellular Hsp70 Inhibitors Promote Cancer Cell Death via Different MechanismsPark et al.Cell Chemical BiologyJuly 26, 2018In BriefDetailed mechanisms by which inhibitors of lysosomal Hsp70 and mitochondrial mortalin promote cancer cell death are unknown. Park et al. show that while an inhibitor of lysosomal Hsp70 induces apoptosis and inhibits autophagy, an inhibitor of mitochondrial Hsp70 induces apoptosis without affecting autophagy. Full-Text PDF Open Archive" @default.
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• W2897350933 title "When Small Molecules Are Like Real Estate: It’s All about Location, Location, Location" @default.
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