Lead generation of heat shock protein 90 inhibitors by a combination of fragment-based approach, virtual screening, and structure-based drug design

Miura, Takaaki; Fukami, Takaaki A.; Hasegawa, Kiyoshi; Ono, Naoki; Suda, Atsushi; Shindo, Hidetoshi; Yoon, Dokyoung; Kim, Sungjin; Na, Young-Jun; Aoki, Yuko; Shimma, Nobuo; Tsukuda, Takuo; Shiratori, Yasuhiko

doi:10.1016/j.bmcl.2011.08.001

Cited by 30 publications

(42 citation statements)

References 17 publications

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“…The jackknife method has been implemented in v1.6 of TITAN and on the basis of these observations, we recommend that users perform error estimates using both approaches and choose the most conservative result. The combined dissociation constant determined from these measurements, 51.1 ± 1.3 µM, was slightly greater than the value of 42 µM previously reported using SPR measurements 41 . This may reflect the effects of attachment to the surface or the biosensor, or the slightly lower ionic strength of the buffer used for SPR (50 mM Tris-based saline, pH 7.6, versus 50 mM sodium phosphate, 50 mM NaCl, pH 7.5).…”

Section: Experimental Application To Hsp90 Ligand Bindingcontrasting

confidence: 68%

“…5B) with the small molecule 1 (Fig. 5A), previously identified in a fragment screen 40 and with a K d of 42 µM previously determined using surface plasmon resonance 41 . An NMR titration was carried out using 70 µM uniformly 1 H, 15 Nlabelled Hsp90 NTD, and a series of fifteen HSQC, SOFAST-HMQC and SOFAST-H(Z/D)QC spectra were acquired at ligand concentrations from 0 to 800 µM (Fig.…”

Section: Experimental Application To Hsp90 Ligand Bindingsupporting

confidence: 55%

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Two-dimensional NMR lineshape analysis of single, multiple, zero and double quantum correlation experiments

Waudby

Ouvry

Davis³

et al. 2019

Preprint

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NMR spectroscopy provides a powerful approach for the characterisation of chemical exchange and molecular interactions by analysis of series of experiments acquired over the course of a titration measurement. The appearance of NMR resonances undergoing chemical exchange depends on the frequency difference relative to the rate of exchange, and in the case of one-dimensional experiments chemical exchange regimes are well established and well known. However, two-dimensional experiments present additional complexity, as at least one additional frequency difference must be considered. Here we provide a systematic classification of chemical exchange regimes in two-dimensional NMR spectra. We highlight important differences between exchange in HSQC and HMQC experiments, that on a practical level result in more severe exchange broadening in HMQC spectra, but show that complementary alternatives to the HMQC are available in the form of HZQC and HDQC experiments. We present the longitudinal relaxation optimised SOFAST-H(Z/D)QC experiment for the simultaneous acquisition of sensitivity-enhanced HZQC and HDQC spectra, and the longitudinal and transverse relaxation optimised BEST-ZQ-TROSY for analysis of large molecular weight systems. We describe the application of these experiments to the characterisation of the interaction between the Hsp90 N-terminal domain and a small molecule ligand, and show that the independent analysis of HSQC, HMQC, HZQC and HDQC experiments provides improved confidence in the fitted dissociation constant and dissociation rate. Joint analysis of such data may provide improved sensitivity to detect and analyse more complex multi-state interaction mechanisms such as induced fit or conformational selection.

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Section: Experimental Application To Hsp90 Ligand Bindingcontrasting

confidence: 68%

Section: Experimental Application To Hsp90 Ligand Bindingsupporting

confidence: 55%

Two-dimensional NMR lineshape analysis of single, multiple, zero and double quantum correlation experiments

Waudby

Ouvry

Davis³

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Recently, through virtual screening and structure-based drug design, we identified CH5164840 as a Hsp90 inhibitor with a novel chemical structure. (32,33) In an initial evaluation, in vitro cell growth inhibition of CH5164840 or erlotinib were examined to determine the sensitivity of NSCLC cell lines with various genotypes, including PC-9 and HCC827 (EGFR DE746-A750), NCI-H292 (wild-type EGFR overexpression), NCI-H1975 (EGFR T790M and L858R mutant), NCI-H1650 (EGFR DE746-A750, PTEN null), NCI-H1781 (HER2 G776insV_G ⁄ C mutant) and A549 (K-ras mutant). The IC 50 values of CH5164840 were found to be 140-550 nM in seven NSCLC cell lines, regardless of genetic mutations, although sensitivities to erlotinib were more variable (IC 50 values 4.7-13000 nM; Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…(30,31) Recently, we identified a novel potent Hsp90 inhibitor, CH5164840. (32,33) In the present study, we report the in vitro and in vivo properties of CH5164840 alone and in combination with erlotinib, including its antitumor activity in EGFRoverexpressing and erlotinib-resistant NSCLC xenograft models.…”

mentioning

confidence: 94%

Enhanced antitumor activity of erlotinib in combination with the Hsp90 inhibitor CH5164840 against non‐small‐cell lung cancer

Ono¹,

Yamazaki²,

Tsukaguchi³

et al. 2013

Cancer Science

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Inhibition of heat shock protein 90 (Hsp90) can lead to degradation of multiple client proteins, which are involved in tumor progression. Epidermal growth factor receptor (EGFR) is one of the most potent oncogenic client proteins of Hsp90. Targeted inhibition of EGFR has shown clinical efficacy in the treatment of patients with non-small-cell lung cancer (NSCLC). However, primary and acquired resistance to the existing EGFR inhibitors is a major clinical problem. In the present study, we investigated the effect of the novel Hsp90 inhibitor CH5164840 on the antitumor activity of erlotinib. The NSCLC cell lines and xenograft models were treated with CH5164840 and erlotinib to examine their mechanisms of action and cell growth inhibition. We found that CH5164840 showed remarkable antitumor activity against NSCLC cell lines and xenograft models. The addition of CH5164840 enhanced the antitumor activity of erlotinib against NCI-H292 EGFR-overexpressing xenograft models. Phosphorylation of Stat3 increased with erlotinib treatment in NCI-H292 cells, which was abrogated by Hsp90 inhibition. Furthermore, in a NCI-H1975 T790M mutation erlotinibresistant model, CH5164840 enhanced the antitumor activity of erlotinib despite the low efficacy of erlotinib treatment alone. In addition, ERK signaling was effectively suppressed by combination treatment with erlotinib and CH5164840 in a NCI-H1975 erlotinibresistant model. Taken together, these data indicate that CH5164840 has potent antitumor activity and is highly effective in combination with erlotinib against NSCLC tumors with EGFR overexpression and mutations. Our results support the therapeutic potential of CH5164840 as a Hsp90 inhibitor for combination therapy with EGFR-targeting agents against EGFR-addicted NSCLC.

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“…Another commonly used assay for FBS is SPR, which detects changes in the refractive index near a sensor surface. SPR fragment-based screening has been utilized to identify novel inhibitors of Hsp90 interactions [46, 47]. In contrast to methods for non-covalent binding, a “tethering” approach is used to detect reversible covalent bonds formed between the cysteine of a target protein and fragment molecules containing a disulfide bond [48].…”

Section: Overcoming Challenges and Current Strategies For Targeting Ppismentioning

confidence: 99%

Targeting protein–protein interactions as an anticancer strategy

Ivanov¹,

Khuri²,

Fu³

2013

Trends in Pharmacological Sciences

339

295

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The emergence and convergence of cancer genomics, targeted therapies, and network oncology have significantly expanded the landscape of protein-protein interaction (PPI) networks in cancer for therapeutic discovery. Extensive biological and clinical investigations have led to the identification of protein interaction hubs and nodes that are critical for the acquisition and maintaining characteristics of cancer essential for cell transformation. Such cancer enabling PPIs have become promising therapeutic targets. With technological advances in PPI modulator discovery and validation of PPI-targeting agents in clinical settings, targeting PPI interfaces as an anticancer strategy has become a reality. Future research directed at genomics-based PPI target discovery, PPI interface characterization, PPI-focused chemical library design, and patient-genomic subpopulation-driven clinical studies is expected to accelerate the development of the next generation of PPI-based anticancer agents for personalized precision medicine. Here we briefly review prominent PPIs that mediate cancer-acquired properties, highlight recognized challenges and promising clinical results in targeting PPIs, and outline emerging opportunities.

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Lead generation of heat shock protein 90 inhibitors by a combination of fragment-based approach, virtual screening, and structure-based drug design

Cited by 30 publications

References 17 publications

Two-dimensional NMR lineshape analysis of single, multiple, zero and double quantum correlation experiments

Two-dimensional NMR lineshape analysis of single, multiple, zero and double quantum correlation experiments

Enhanced antitumor activity of erlotinib in combination with the Hsp90 inhibitor CH5164840 against non‐small‐cell lung cancer

Targeting protein–protein interactions as an anticancer strategy

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