4-Amino derivatives of the Hsp90 inhibitor CCT018159

Barril, Xavier; Beswick, Mandy; Collier, Adam J.; Drysdale, Martin J.; Dymock, Brian; Fink, Alexandra; Grant, Kate; Howes, Ruth; Jordan, Allan M.; Massey, Andrew; Surgenor, A.E.; Wayne, Joanne; Workman, Paul; Wright, Lisa

doi:10.1016/j.bmcl.2006.01.099

Cited by 79 publications

(56 citation statements)

References 13 publications

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“…[74] Medicinal chemistry efforts led to identification of the more potent 5-amido analogue of CCT018159 [75] (VER-49009, IC 50 = 0.14 mm) and the 4-amino analogue 9 (IC 50 = 0.6 mm; Figure 8). [76] …”

Section: Purine Derivativesmentioning

confidence: 97%

Hsp90 as a Target for Drug Development

2006

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Section: Purine Derivativesmentioning

confidence: 97%

Hsp90 as a Target for Drug Development

2006

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“…However, despite the high cellular activity and clinical progression of 17-allylaminogeldanamycin 18 , it has several limitations, for example, poor solubility, hepatotoxicity and extensive metabolism. These issues have led to significant efforts to identify novel rationally designed small molecular inhibitors of Hsp90 19 . The main focus of recent efforts toward the development of new Hsp90 inhibitors concentrate on structure-based ligand design [20][21][22] and highthroughput screening 23 , with a few ligand-based examples 24,25 .…”

Section: Introductionmentioning

confidence: 99%

Discovery of new heat shock protein 90 inhibitors using virtual co-crystallized pharmacophore generation

Al-Sha’er

Mansi

Khanfar

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The pharmacophoric features of the virtual cocrystallized protein of 178 Hsp90 proteins were obtained from the protein data bank and explored to generate 1260 pharmacophores evaluated using the decoy list composed of 1022 compounds. Accordingly, 51 pharmacophores were selected with high receiver operating characteristic (ROC) value for further processing. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing a self-consistent quantitative structure-activity relationship (QSAR) of optimal predictive potential (R The fifth generated pharmacophoric model from Hsp90 protein 2XJX (2XJX_2_05), and the forth generated cocrystallized pharmacophoric model from Hsp90 protein 4LWF (4LWF_2_04) with area under the curve AUC-ROC values 0.812 and 0.876, respectively were selected to be used as a searching tool sequentially of the National Cancer Institute (NCI) database. The captured hits were mapped based on successful hypotheses and the best predicted hits were selected. Twenty-four hits showed Hsp90 inhibition, 15 hits were measured with low micromolar IC 50 ranged from 5.0 mM to 77.1 mM

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“…The MD simulation was carried out to ensure the stability of ligand 3 in the active site of proteins and also to compare its interaction modes of PK7242 and inhibitor 2 with p53 and Hsp90, respectively [31]. The docking's best conformation was chosen to carry out MD simulations (in terms of the lowest binding energy and the best orientation of the ligand in the active site).…”

Section: Simulation Analysismentioning

confidence: 99%