Novel Adenosine-Derived Inhibitors of 70 kDa Heat Shock Protein, Discovered Through Structure-Based Design

Williamson, D.S.; Borgognoni, Jenifer; Clay, Alexandra; Daniels, Zoe; Dokurno, P.; Drysdale, Martin J.; Foloppe, Nicolas; Francis, Geraint L.; Graham, Christopher; Howes, Rob; Macías, A.; Murray, James B.; Parsons, Rachel; Shaw, T.; Surgenor, A.E.; Terry, Lindsey; Wang, Yikang; Wood, Mike; Massey, Andrew

doi:10.1021/jm801627a

Cited by 205 publications

(277 citation statements)

References 22 publications

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“…For example, the compound VER-155008 was identified as an ATP analog that overlaps with the ATP binding site of HSP70 and competes for ATP binding of HSP70. 10 This compound likely inhibits HSP70 activity by keeping this protein in a state that has reduced affinity for substrate. Conversely, the compound MKT-077 binds near but not at the ATP binding site, and preferentially binds to the ADP-bound form of this enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…10 Like PES, VER-155008 is preferentially cytotoxic to cancer cells but not normal cells, and reduces HSP90 client protein levels in tumor cells. 11 The rhodacyanine dye derivative MKT-077 was first discovered as a compound that was cytotoxic to cancer cells but not normal cells, and later shown to bind to the mitochondrial HSP70 member HSPA9 (also called GRP75 or mortalin).…”

Section: Research Papermentioning

confidence: 99%

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Comparison of the activity of three different HSP70 inhibitors on apoptosis, cell cycle arrest, autophagy inhibition, and HSP90 inhibition

Budina-Kolomets

Balaburski

Bondar

et al. 2013

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

Section: Research Papermentioning

confidence: 99%

Comparison of the activity of three different HSP70 inhibitors on apoptosis, cell cycle arrest, autophagy inhibition, and HSP90 inhibition

Budina-Kolomets

Balaburski

Bondar

et al. 2013

Cancer Biology & Therapy

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“…Cell proliferation was determined using the sulforhodamine B (SRB) assay. VER-155008 and VER-82160 were synthesized as previously described [22,23].…”

Section: Methodsmentioning

confidence: 99%

“…The activity of VER-155008 was determined against Hsp70 and Hsp90 as previously described [23]. Hsc70 (aa 5-381) and Grp78 (ATPase domain) were cloned and expressed as follows.…”

Section: Methodsmentioning

confidence: 99%

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A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

Massey¹,

Williamson²,

Browne³

et al. 2009

Cancer Chemother Pharmacol

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273

254

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Purpose The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in cancer is well documented. Dual targeting of Hsc70 and Hsp70 with siRNA induces proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition. Methods We have previously described the discovery and synthesis of novel adenosine-derived inhibitors of the 70 kDa family of heat shock proteins; the first inhibitors described to target the ATPase binding domain. The in vitro activity of VER-155008 was evaluated in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors. Results VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI 50 s in the range 5.3-14.4 lM, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule Hsp90 inhibitor in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level. Conclusion These data suggest that small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/ Hsp70 inhibition remain to be determined.

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GRP78 protects a disintegrin and metalloprotease 17 against protein‐disulfide isomerase A6 catalyzed inactivation

et al. 2017

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The shedding of ectodomains is a crucial mechanism in many physiological and pathological events. A disintegrin and metalloprotease-17 (ADAM17) is a key sheddase involved in essential processes, such as development, regeneration, and immune defense. ADAM17 exists in two conformations which differ in their disulfide connection in the membrane-proximal domain (MPD). Protein-disulfide isomerases (PDIs) on the cell surface convert the open MPD into a rigid closed form, which corresponds to inactive ADAM17. ADAM17 is expressed in its open activatable form in the endoplasmic reticulum (ER) and consequently must be protected against ER-resident PDI activity. Here, we show that the chaperone 78-kDa glucose-regulated protein (GRP78) protects the MPD against PDI-dependent disulfide-bond isomerization by binding to this domain and, thereby, preventing ADAM17 inhibition.

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Novel Adenosine-Derived Inhibitors of 70 kDa Heat Shock Protein, Discovered Through Structure-Based Design

Cited by 205 publications

References 22 publications

Comparison of the activity of three different HSP70 inhibitors on apoptosis, cell cycle arrest, autophagy inhibition, and HSP90 inhibition

Comparison of the activity of three different HSP70 inhibitors on apoptosis, cell cycle arrest, autophagy inhibition, and HSP90 inhibition

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

GRP78 protects a disintegrin and metalloprotease 17 against protein‐disulfide isomerase A6 catalyzed inactivation

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