Radiosynthesis of the iodine‐124 labeled Hsp90 inhibitor PU‐H71

Taldone, Tony; Zatorska, Danuta; Ochiana, Stefan O.; Smith‐Jones, Peter; Koziorowski, Jacek; Dunphy, Mark; Zanzonico, Pat; Bolaender, Alexander; Lewis, Jason S.; Larson, Steven M.; Chiosis, Gabriela; Pillarsetty, Nagavarakishore

doi:10.1002/jlcr.3369

Cited by 20 publications

(19 citation statements)

References 18 publications

(21 reference statements)

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“…24), and the radiolabelled PU-H71-derivative 124 I-PU-H71 (ref. 25) were generated as previously described. The specificity of PU-H71 for HSP90 and over other proteins was extensively analysed 7 .…”

Section: Methodsmentioning

confidence: 99%

The epichaperome is an integrated chaperome network that facilitates tumour survival

Rodina

Wang

Yan

et al. 2016

Nature

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Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes—dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery1–6. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy7–17. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically ‘rewired’ to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.

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Section: Methodsmentioning

confidence: 99%

The epichaperome is an integrated chaperome network that facilitates tumour survival

Rodina

Wang

Yan

et al. 2016

Nature

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231

531

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“…Three such assays have been developed and trans-lated to clinic: PU-PET for solid tumors, to detect the epichaperome biomarker by PET imaging (Fig. 5a) (https://clinicaltrials.gov/identifier NCT01269593) (46,106); PU-FITC for liquid tumors, to detect the epichaperome by flow cytometry (Fig. 5b) (46,96); and IEF for biopsies, to detect the epichaperome by native IEF chromatography (Figs.…”

Section: Epichaperome As a Tumor Target And Biomarkermentioning

confidence: 99%

Chaperome heterogeneity and its implications for cancer study and treatment

Wang

Rodina

Dunphy³

et al. 2019

Journal of Biological Chemistry

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The chaperome is the collection of proteins in the cell that carry out molecular chaperoning functions. Changes in the interaction strength between chaperome proteins lead to an assembly that is functionally and structurally distinct from each constituent member. In this review, we discuss the epichaperome, the cellular network that forms when the chaperome components of distinct chaperome machineries come together as stable, functionally integrated, multimeric complexes. In tumors, maintenance of the epichaperome network is vital for tumor survival, rendering them vulnerable to therapeutic interventions that target critical epichaperome network components. We discuss how the epichaperome empowers an approach for precision medicine cancer trials where a new target, biomarker, and relevant drug candidates can be correlated and integrated. We introduce chemical biology methods to investigate the heterogeneity of the chaperome in a given cellular context. Lastly, we discuss how ligand-protein binding kinetics are more appropriate than equilibrium binding parameters to characterize and unravel chaperome targeting in cancer and to gauge the selectivity of ligands for specific tumor-associated chaperome pools. This is the ninth article in the JBC Reviews series "Molecular chaperones and protein quality control." G. C. has partial ownership in Samus Therapeutics Inc., which develops epichaperome inhibitors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 1 Supported by the Lymphoma Research Foundation. 2 Supported by National Institutes of Health Grants R01 CA172546 and R01 CA102031 and the Irma T. Hirschl/Monique Weill-Caulier Trust and Unravel Pediatric Cancer Foundation.

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“…Further analysis of PU3 and its interaction with HSP90α resulted in the synthesis of PU-H71 “6-Amino-8-[(6-iodo-1,3-benzodioxol-5-yl)thio]- N -(1-methylethyl)-9 H -purine-9-propanamine”. Interestingly, PU-H71 is only required in minute concentrations to inhibit HSP90α with a higher affinity towards tumourigenic cells 25 , 29 . PU-H71 is a newer water-soluble purine-analogue and is considered the most promising HSP90 inhibitor, having potent selectivity for HSP90 in epichaperome networks 30 .…”

Section: Introductionmentioning

confidence: 99%

Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): preclinical insights

Anwar

Shalaby

Embaby

et al. 2020

Sci Rep

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Prodigiosin, a secondary metabolite red pigment produced by Serratia marcescens, has an interesting apoptotic efficacy against cancer cell lines with low or no toxicity on normal cells. HSP90α is known as a crucial and multimodal target in the treatment of TNBC. Our research attempts to assess the therapeutic potential of prodigiosin/PU-H71 combination on MDA-MB-231 cell line. The transcription and protein expression levels of different signalling pathways were assessed. Treatment of TNBC cells with both drugs resulted in a decrease of the number of adherent cells with apoptotic effects. Prodigiosin/PU-H71 combination increased the levels of caspases 3,8 and 9 and decreased the levels of mTOR expression. Additionally, there was a remarkable decrease of HSP90α transcription and expression levels upon treatment with combined therapy. Also, EGFR and VEGF expression levels decreased. This is the first study to show that prodigiosin/PU-H71 combination had potent cytotoxicity on MDA-MB-231 cells; proving to play a paramount role in interfering with key signalling pathways in TNBC. Interestingly, prodigiosin might be a potential anticancer agent to increase the sensitivity of TNBC cells to apoptosis. This study provides a new basis for upcoming studies to overcome drug resistance in TNBC cells.

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Radiosynthesis of the iodine‐124 labeled Hsp90 inhibitor PU‐H71

Cited by 20 publications

References 18 publications

The epichaperome is an integrated chaperome network that facilitates tumour survival

The epichaperome is an integrated chaperome network that facilitates tumour survival

Chaperome heterogeneity and its implications for cancer study and treatment

Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): preclinical insights

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