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  • 1
    Language: English
    In: Cancer Drug Design and Discovery
    Keywords: Cancer Treatment ; Antineoplastic Agents ; Ionizing Radiation ; Tumor Proteins
    ISBN: 978-0-12-397228-6
    Source: Gale Virtual Reference Library (GVRL)
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  • 2
    Language: English
    In: Cancer Drug Design and Discovery, Chapter 13, pp.391-426
    Description: Cancer drug discovery activities in the postgenomic era have sought to identify small molecules able to modulate molecular targets identified as being intimately linked to the “hallmark” characteristics of cancer. The tractability of protein–protein interactions as molecular targets for small-molecule drugs has been examined, raising the possibility that small molecules, able to bind with sufficient affinity to hotspot clusters, would be able to antagonize a given protein–protein interaction. The therapeutic hypothesis for MDM2–p53 inhibition proposes that a potent inhibitor of the protein–protein interaction will liberate p53 from the repressive control of MDM2, and subsequently activate p53-mediated cell death in the tumor. A number of small-molecule MDM2–p53 inhibitors have been discovered and clinical trials are ongoing to establish their efficacy.
    Keywords: Cancer drug discovery ; protein–protein interaction inhibitors ; MDM2–p53 ; MDMX–p53
    ISBN: 978-0-12-396521-9
    ISBN: 978-0-12-397228-6
    Source: ScienceDirect (Elsevier B.V.)
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  • 3
    Language: English
    In: 2012, Vol.7(10), p.e45539
    Description: Tip60 (KAT5) is a histone acetyltransferase (HAT enzyme) involved in multiple cellular processes including transcriptional regulation, DNA damage repair and cell signalling. In prostate cancer, aggressive cases over-express Tip60 which functions as an androgen receptor co-activator via direct acetylation of lysine residues within the KLKK motif of the receptor hinge region. The purpose of this study was to identify and characterise a Tip60 acetylase inhibitor. High-throughput screening revealed an isothiazole that inhibited both Tip60 and p300 HAT activity. This substance (initially identified as 4-methyl-5-bromoisothiazole) and other isothiazoles were synthesised and assayed against Tip60. Although an authentic sample of 4-methyl-5-bromoisothiazole was inactive against Tip60, in an in vitro HAT assay, 1,2-bis(isothiazol-5-yl)disulfane (NU9056) was identified as a relatively potent inhibitor (IC 50 2 µM). Cellular activity was confirmed by analysis of acetylation of histone and non-histone proteins in a prostate cancer cell line model. NU9056 treatment inhibited cellular proliferation in a panel of prostate cancer cell lines (50% growth inhibition, 8–27 µM) and induced apoptosis via activation of caspase 3 and caspase 9 in a concentration- and time-dependent manner. Also, decreased androgen receptor, prostate specific antigen, p53 and p21 protein levels were demonstrated in response to treatment with NU9056. Furthermore, pre-treatment with NU9056 inhibited both ATM phosphorylation and Tip60 stabilization in response to ionising radiation. Based on the activity of NU9056 and the specificity of the compound towards Tip60 relative to other HAT enzymes, these chemical biology studies have identified Tip60 as a potential therapeutic target for the treatment of prostate cancer.
    Keywords: Research Article ; Biology ; Medicine ; Genetics And Genomics ; Molecular Biology ; Urology ; Biotechnology ; Oncology ; Pharmacology ; Biochemistry
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Chemistry – A European Journal, 17 February 2014, Vol.20(8), pp.2311-2317
    Description: Small‐molecule drug discovery requires reliable synthetic methods for attaching amino compounds to heterocyclic scaffolds. Trifluoroacetic acid‐2,2,2‐trifluoroethanol (TFA‐TFE) is as an effective combination for achieving SAr reactions between anilines and heterocycles (e.g., purines and pyrimidines) substituted with a leaving group (fluoro‐, chloro‐, bromo‐ or alkylsulfonyl). This method provides a variety of compounds containing a “kinase‐privileged fragment” associated with potent inhibition of kinases. TFE is an advantageous solvent because of its low nucleophilicity, ease of removal and ability to solubilise polar substrates. Furthermore, TFE may assist the breakdown of the Meisenheimer–Jackson intermediate by solvating the leaving group. TFA is a necessary and effective acidic catalyst, which activates the heterocycle by N‐protonation without deactivating the aniline by conversion into an anilinium species. The TFA‐TFE methodology is compatible with a variety of functional groups and complements organometallic alternatives, which are often disadvantageous because of the expense of reagents, the frequent need to explore diverse sets of reaction conditions, and problems with product purification. In contrast, product isolation from TFA‐TFE reactions is straightforward: evaporation of the reaction mixture, basification and chromatography affords analytically pure material. A total of 45 examples are described with seven discrete heterocyclic scaffolds and 2‐, 3‐ and 4‐substituted anilines giving product yields that are normally in the range 50–90 %. Reactions can be performed with either conventional heating or microwave irradiation, with the latter often giving improved yields. : Trifluoroacetic acid/2,2,2‐trifluoroethanol is an effective combination for achieving SAr reactions between anilines and heterocycles (e.g., purines and pyrimidines) substituted with a suitably positioned leaving group (fluoro‐, chloro‐, bromo‐ or alkylsulfonyl; see scheme).
    Keywords: Catalysis ; Heterocyclic Drugs ; Sar ; Synthetic Methods ; Trifluoroethanol
    ISSN: 0947-6539
    E-ISSN: 1521-3765
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  • 5
  • 6
  • 7
    Language: English
    In: Future medicinal chemistry, 2015, Vol.7(5), pp.631-45
    Description: Potent and selective small-molecule inhibitors of the p53-MDM2 interaction intended for the treatment of p53 wild-type tumors have been designed and optimized in a number of chemical series. This review details recent disclosures of compounds in advanced optimization and features key series that have given rise to clinical trial candidates. The structure-activity relationships for inhibitor classes are discussed with reference to x-ray structures, and common structural features are identified.
    Keywords: Antineoplastic Agents -- Chemistry ; Neoplasms -- Drug Therapy ; Protein Interaction Maps -- Drug Effects ; Proto-Oncogene Proteins C-Mdm2 -- Metabolism ; Tumor Suppressor Protein P53 -- Metabolism
    ISSN: 17568919
    E-ISSN: 1756-8927
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  • 8
    Language: English
    In: Journal of medicinal chemistry, 09 January 2014, Vol.57(1), pp.56-70
    Description: Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O(6)-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a "reverse" binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these "reverse" binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.
    Keywords: Cyclin-Dependent Kinase 2 -- Antagonists & Inhibitors ; Protein Kinase Inhibitors -- Chemical Synthesis
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 9
    Language: English
    In: Journal of medicinal chemistry, 22 August 2013, Vol.56(16), pp.6386-401
    Description: Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH₂)nNR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC₅₀ = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors.
    Keywords: DNA-Activated Protein Kinase -- Antagonists & Inhibitors ; Morpholines -- Pharmacology ; Phosphatidylinositol 3-Kinases -- Antagonists & Inhibitors ; Protein Kinase Inhibitors -- Pharmacology
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 10
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