Discovery and Optimization of Small Molecules Targeting the Protein–Protein Interaction of Heat Shock Protein 90 (Hsp90) and Cell Division Cycle 37 as Orally Active Inhibitors for the Treatment of Colorectal Cancer

Wang, Lei; Jiang, Jingsheng; Zhang, Lixiao; Zhang, Qiuyue; Zhou, Jianrui; Li, Li; Xu, Xiu; You, Qidong

doi:10.1021/acs.jmedchem.9b01659

Cited by 30 publications

(33 citation statements)

References 35 publications

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“…Hsp90/Cdc37 interface inhibition represents an alternative strategy to target Hsp90, but without the problematic induction of the ‘heat shock response’ which is seen with ATP-pocket inhibitors. Based on conglobatin A toxicity data and the recently-published small molecule inhibitor (18h) [ 27 ], the targeting of the Hsp90/Cdc37 interface may be pharmacologically advantageous. The here-identified drug-like small molecules from different scaffolds may thus help to further validate the Hsp90/Cdc37 interface for its low on-target toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…This sterical component seems to be emulated by the adamantly-containing compound ×6506 that we have discovered. Like conglobatin A, the more recent inhibitors DDO-5936 and compound (18 h), and our here-identified compounds engage residues Glu47 and Gln133 on Hsp90, which are otherwise critical to stabilize the complex with Cdc37 [ 26 , 27 ]. The currently most potent small molecule Hsp90/Cdc37 interface inhibitor, compound (18 h) (K d = 0.5 μM) was more efficacious in reducing the growth of HCT116 cell-derived colorectal cancer xenografts than its predecessor, DDO-5936.…”

Section: Discussionmentioning

confidence: 99%

“…The binding mode of the tool compound DDO-5936 to Hsp90 (K d = 3.86 μM) was resolved using nuclear magnetic resonance (NMR) spectroscopy and mutagenesis, revealing a major engagement of Glu47, Arg46 and Gln133 of Hsp90, which directly interferes with residues previously identified to be critical for the Hsp90/Cdc37 interaction [ 18 ]. Further improvement for affinity and pharmacological properties led to an orally-available compound referred to as 18 h, with a submicromolar affinity to Hsp90 (K d = 0.5 μM) [ 27 ]. Despite their apparent proximity to the ATP-binding pocket, no disruption of ATP-pocket binders was observed.…”

Section: Introductionmentioning

confidence: 99%

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Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling

Siddiqui

Parkkola

Vukić

et al. 2021

Cancers

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The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1α. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1α-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 μM —44 μM in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling

Siddiqui

Parkkola

Vukić

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…In addition, inhibition of the Hsp90-Cdc37 complex by DDO-5936 results in downregulation of cyclin-dependent kinase 4 and consequent inhibition of cell proliferation through Cdc37dependent cell cycle arrest, as well as in vivo antitumor potency in a xenograft model [99]. Later, the same group developed compound 23 with improved binding affinity and antiproliferative activity, preferable stability in plasma and microsomes, and oral efficacy in vivo, compared with DDO-5936 [100]. Based on the binding mode of compound 21, they recently discovered a hydrophobic pocket centered on Phe213 of Hsp90 that contributes to the binding affinity of Hsp90-Cdc37 interaction inhibitors [101].…”

Section: Small-molecule Inhibitorsmentioning

confidence: 99%

Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases

Wang

Bergkvist

Kumar

et al. 2021

Cells

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The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, assisting with intracellular transport, and interfering with protein aggregation or degradation. Heat shock protein 70 kDa (Hsp70) and 90 kDa (Hsp90) are two of the most important chaperones whose functions are dependent on ATP hydrolysis and collaboration with their co-chaperones. Numerous studies implicate Hsp70, Hsp90, and their co-chaperones in neurodegenerative diseases. Targeting the specific protein–protein interactions between chaperones and their particular partner co-chaperones with small molecules provides an opportunity to specifically modulate Hsp70 or Hsp90 function for neurodegenerative diseases. Here, we review the roles of co-chaperones in Hsp70 or Hsp90 chaperone cycles, the impacts of co-chaperones in neurodegenerative diseases, and the development of small molecules modulating chaperone/co-chaperone interactions. We also provide a future perspective of drug development targeting chaperone/co-chaperone interactions for neurodegenerative diseases.

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“…Such inhibitors could therefore induce biological effects that are distinct from ATP site Hsp90 inhibitors and hence result in potential therapeutic advantages. This is evidenced by the recent discovery and characterization of small-molecules that inhibit the interaction between Hsp90 and its cochaperone Cdc37 33 .…”

mentioning

confidence: 99%

Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches

Darby

Vidler

Simpson

et al. 2020

Sci Rep

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Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic ‘client’ proteins. Inhibition of Hsp90 by small-molecule drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, positively charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native ‘carboxylate clamp’ interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping 1H–15N HSQC chemical shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chemically challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors.

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Discovery and Optimization of Small Molecules Targeting the Protein–Protein Interaction of Heat Shock Protein 90 (Hsp90) and Cell Division Cycle 37 as Orally Active Inhibitors for the Treatment of Colorectal Cancer

Cited by 30 publications

References 35 publications

Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling

Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling

Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases

Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches

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