Fearon, D., Westwood, I.M., van Montfort, R.L., Bayliss, R., Jones, K. & Bavetsias, V.
(2018). Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition. Bioorganic & medicinal chemistry,
Stork, G., Yamashita, A., Hanson, R.M., Phan, L., Phillips, E., Dubé, D., Bos, P.H., Clark, A.J., Gough, M., Greenlee, M.L., et al.
(2017). Synthetic Study toward Total Synthesis of (±)-Germine: Synthesis of (±)-4-Methylenegermine. Organic letters,
Pettinger, J., Le Bihan, Y.-., Widya, M., van Montfort, R.L., Jones, K. & Cheeseman, M.D.
(2017). An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56. Angewandte chemie-international edition,
Pettinger, J., Jones, K. & Cheeseman, M.D.
(2017). Auf Lysin zielende, kovalente Inhibitoren. Angewandte chemie,
Jones, A.M., Westwood, I.M., Osborne, J.D., Matthews, T.P., Cheeseman, M.D., Rowlands, M.G., Jeganathan, F., Burke, R., Lee, D., Kadi, N., et al.
(2016). A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms. Scientific reports,
Cheeseman, M.D., Westwood, I.M., Barbeau, O., Rowlands, M., Dobson, S., Jones, A.M., Jeganathan, F., Burke, R., Kadi, N., Workman, P., et al.
(2016). Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70. J med chem,
HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner..
Andrikopoulos, P., Kieswich, J., Harwood, S.M., Baba, A., Matsuda, T., Barbeau, O., Jones, K., Eccles, S.A. & Yaqoob, M.M.
(2015). Endothelial Angiogenesis and Barrier Function in Response to Thrombin Require Ca2+Influx through the Na+/Ca2+Exchanger. Journal of biological chemistry,
Cheeseman, M.D., Faisal, A., Rayter, S., Barbeau, O.R., Kalusa, A., Westlake, M., Burke, R., Swan, M., van Montfort, R., Linardopoulos, S., et al.
(2014). Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines. Bioorg med chem lett,
The metal-dependent phosphatase PPM1D (WIP1) is an important oncogene in cancer, with over-expression of the protein being associated with significantly worse clinical outcomes. In this communication we describe the discovery and optimization of novel 2,4-bisarylthiazoles that phenocopy the knockdown of PPM1D, without inhibiting its phosphatase activity. These compounds cause growth inhibition at nanomolar concentrations, induce apoptosis, activate p53 and display impressive cell-line selectivity. The results demonstrate the potential for targeting phenotypes in drug discovery when tackling challenging targets or unknown mechanisms. .
Hickin, J.A., Ahmed, A., Fucke, K., Ashcroft, M. & Jones, K.
(2014). The synthesis and structure revision of NSC-134754. Chem commun (camb),
The synthesis of emetine analogue NSC-134754, a potent inhibitor of the HIF pathway, has been accomplished and its structure reassigned. The stereochemistry of NSC-134754 has been assigned for the first time using X-ray crystallography and it has been demonstrated that only one diastereoisomer is active against HIF. .
Couty, S., Westwood, I.M., Kalusa, A., Cano, C., Travers, J., Boxall, K., Chow, C.L., Burns, S., Schmitt, J., Pickard, L., et al.
(2013). The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design. Oncotarget,
The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases..
Silva-Santisteban, M.C., Westwood, I.M., Boxall, K., Brown, N., Peacock, S., McAndrew, C., Barrie, E., Richards, M., Mirza, A., Oliver, A.W., et al.
(2013). Fragment-based screening maps inhibitor interactions in the ATP-binding site of checkpoint kinase 2. Plos one,
Checkpoint kinase 2 (CHK2) is an important serine/threonine kinase in the cellular response to DNA damage. A fragment-based screening campaign using a combination of a high-concentration AlphaScreen™ kinase assay and a biophysical thermal shift assay, followed by X-ray crystallography, identified a number of chemically different ligand-efficient CHK2 hinge-binding scaffolds that have not been exploited in known CHK2 inhibitors. In addition, it showed that the use of these orthogonal techniques allowed efficient discrimination between genuine hit matter and false positives from each individual assay technology. Furthermore, the CHK2 crystal structures with a quinoxaline-based fragment and its follow-up compound highlight a hydrophobic area above the hinge region not previously explored in rational CHK2 inhibitor design, but which might be exploited to enhance both potency and selectivity of CHK2 inhibitors..
Evans, L.E., Cheeseman, M.D. & Jones, K.
(2012). N-N bond-forming cyclization for the one-pot synthesis of N-aryl[3,4-d]pyrazolopyrimidines. Org lett,
An efficient one-pot synthesis of N-aryl[3,4-d]pyrazolopyrimidines in good yield and under mild reaction conditions is described. By exploiting electron-deficient hydroxylamines, the substituted oxime products were formed with very high E-diastereoselectivity. The key step utilizes a cyclization reaction upon an oxime derived from hydroxylamine-O-sulfonic acid to form the N-N bond of the product..
Francis, N.-., Rowlands, M., Workman, P., Jones, K. & Aherne, W.
(2012). Small-molecule inhibitors of the protein methyltransferase SET7/9 identified in a high-throughput screen. J biomol screen,
Aberrant expression of chromatin-modifying enzymes (CMEs) is associated with a range of human diseases, including cancer. CMEs are now an important target area in drug discovery. Although the role that histone and protein (lysine) methyltransferases (PMTs) play in the regulation of transcription and cell growth is increasingly recognized, few small-molecule inhibitors of this class of enzyme have been reported. Here we describe an assay suitable for primary compound screening for the identification of PMT inhibitors. The assay followed the methylation of histones in the presence of the PMT SET7/9 and the radioactive cofactor S-adenosyl-methionine using scintillating microplates (FlashPlate) and was used to screen approximately 65 000 compounds (% coefficient of variation = 10%; Z' = 0.6). The hits identified from a library of more than 63 000 diverse small molecules included a series of rhodanine compounds with micromolar activity. A screen of the National Cancer Institute Diversity Set (2000 compounds) identified an orsein derivative that inhibited SET7/9 (~20 µM) and showed modest growth inhibition associated with the expected cellular phenotype of reduced histone methylation in a human tumor cell line. The assay represents a useful tool for the identification of inhibitors of PMT activity..
Rowlands, M., McAndrew, C., Prodromou, C., Pearl, L., Kalusa, A., Jones, K., Workman, P. & Aherne, W.
(2010). Detection of the ATPase activity of the molecular chaperones Hsp90 and Hsp72 using the TranscreenerTM ADP assay kit. J biomol screen,
The molecular chaperone heat shock protein 90 (Hsp90) is required for the correct folding and stability of a number of client proteins that are important for the growth and maintenance of cancer cells. Heat shock protein 72 (Hsp72), a co-chaperone of Hsp90, is also emerging as an attractive cancer drug target. Both proteins bind and hydrolyze adenosine triphosphate (ATP), and ATPase activity is essential for their function. Inhibition of Hsp90 ATPase activity leads to the degradation of client proteins, resulting in cell growth inhibition and apoptosis. Several small-molecule inhibitors of the ATPase activity of Hsp90 have been described and are currently being evaluated clinically for the treatment of cancer. A number of methods for the measurement of ATPase activity have been previously used, but not all of these are ideally suited to screening cascades in drug discovery projects. The authors have evaluated the use of commercial reagents (Transcreener ADP) for the measurement of ATPase activity of both yeast and human Hsp90 (ATP K(m) approximately 500 microM) and human Hsp72 (ATP K(m) ~1 microM). The low ATPase activity of human Hsp90 and its stimulation by the co-chaperone Aha1 was measured with ease using reduced incubation times, generating robust data (Z' = 0.75). The potency of several small-molecule inhibitors of both Hsp90 and Hsp72 was determined using the Transcreener reagents and compared well to that determined using other assay formats..
Jones, K. & McHardy, T.
(2010). Cancer Drug Discovery 2010: from molecules to medicine. Expert rev clin pharmacol,
This article provides an overview of a recent 1-day symposium on the current status and the future prospects for small-molecule therapeutics in oncology. Presentations included aspects of kinase inhibition, the targeting of G-quadruplexes, oxygen sensing as a therapeutic target and sulfatase inhibitors for hormone-dependent breast cancer..
Powers, M.V., Jones, K., Barillari, C., Westwood, I., van Montfort, R.L. & Workman, P.
(2010). Targeting HSP70: the second potentially druggable heat shock protein and molecular chaperone?. Cell cycle,
The HSF1-mediated stress response pathway is steadily gaining momentum as a critical source of targets for cancer therapy. Key mediators of this pathway include molecular chaperones such as heat shock protein (HSP) 90. There has been considerable progress in targeting HSP90 and the preclinical efficacy and signs of early clinical activity of HSP90 inhibitors have provided proof-of-concept for targeting this group of proteins. The HSP70 family of molecular chaperones are also key mediators of the HSF-1-stress response pathway and have multiple additional roles in protein folding, trafficking and degradation, as well as regulating apoptosis. Genetic and biochemical studies have supported the discovery of HSP70 inhibitors which have the potential for use as single agents or in combination to enhance the effects of classical chemotherapeutic or molecularly targeted agents including HSP90 inhibitors. Here we provide a perspective on the progress made so far in designing agents which target the HSP70 family..
Ahmad, N.M. & Jones, K.
(2010). An efficient synthesis of thiazolo[3,2-a]pyrimidinones. Tetrahedron lett,
A series of thiazolo[3,2-a]pyrimidinones was synthesised in a two-step procedure, using Eaton's reagent to effect cyclisation of 2-aminothiazoles. The use of relatively low temperatures, facile product isolation and short reaction times make this cyclisation procedure a particularly attractive option over more conventional methods. (C) 2010 Elsevier Ltd. All rights reserved..
Mirizzi, D., Hilton, S.T. & Jones, K.
(2010). Heteroaryl Radicals Review. Adv heterocycl chem,
Kalusa, A., Chessum, N. & Jones, K.
(2008). An efficient synthesis of 2,3-diaryl (3H)-quinazolin-4-ones via imidoyl chlorides. Tetrahedron lett,
A practical and efficient three step synthetic route to 2,3-diaryl (3H)-quinazolin-4-ones has been developed. The key step involves microwave-assisted condensation of an imidoyl chloride with an aryl amine. This methodology affords the products cleanly and in high yields. (C) 2008 Elsevier Ltd. All rights reserved..
Rayter, S., Elliott, R., Travers, J., Rowlands, M.G., Richardson, T.B., Boxall, K., Jones, K., Linardopoulos, S., Workman, P., Aherne, W., et al.
(2008). A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D. Oncogene,
The PPM1D gene is aberrantly amplified in a range of common cancers and encodes a protein phosphatase that is a potential therapeutic target. However, the issue of whether inhibition of PPM1D in human tumour cells that overexpress this protein compromises their viability has not yet been fully addressed. We show here, using an RNA interference (RNAi) approach, that inhibition of PPM1D can indeed reduce the viability of human tumour cells and that this effect is selective; tumour cell lines that overexpress PPM1D are sensitive to PPM1D inhibition whereas cell lines with normal levels are not. Loss of viability associated with PPM1D RNAi in human tumour cells occurs via the activation of the kinase P38. To identify chemical inhibitors of PPM1D, a high-throughput screening of a library of small molecules was performed. This strategy successfully identified a compound that selectively reduces viability of human tumour cell lines that overexpress PPM1D. As expected of a specific inhibitor, the toxicity to PPM1D overexpressing cell lines after inhibitor treatment is P38 dependent. These results further validate PPM1D as a therapeutic target and identify a proof-of-principle small molecule inhibitor..
Eccles, S.A., Massey, A., Raynaud, F.I., Sharp, S.Y., Box, G., Valenti, M., Patterson, L., de Haven Brandon, A., Gowan, S., Boxall, F., et al.
(2008). NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer res,
We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1alpha, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials..
Hardcastle, A., Tomlin, P., Norris, C., Richards, J., Cordwell, M., Boxall, K., Rowlands, M., Jones, K., Collins, I., McDonald, E., et al.
(2007). A duplexed phenotypic screen for the simultaneous detection of inhibitors of the molecular chaperone heat shock protein 90 and modulators of cellular acetylation. Mol cancer ther,
Histone deacetylases (HDACs), histone acetyltransferases (HATs), and the molecular chaperone heat shock protein 90 (HSP90) are attractive anticancer drug targets. High-throughput screening plays a pivotal role in modern molecular mechanism-based drug discovery. Cell-based screens are particularly useful in that they identify compounds that are permeable and active against the selected target or pathway in a cellular context. We have previously developed time-resolved fluorescence cell immunosorbent assays (TRF-Cellisas) for compound screening and pharmacodynamic studies. These assays use a primary antibody to the single protein of interest and a matched secondary immunoglobulin labeled with an europium chelate (Eu). The availability of species-specific secondary antibodies labeled with different lanthanide chelates provides the potential for multiplexing this type of assay. The approach has been applied to the development of a 384-well duplexed cell-based screen to simultaneously detect compounds that induce the co-chaperone HSP70 as a molecular marker of potential inhibitors of HSP90 together with those that modulate cellular acetylation (i.e., potential inhibitors of histone deacetylase or histone acetyltransferase activity). The duplexed assay proved reliable in high-throughput format and approximately 64,000 compounds were screened. Following evaluation in secondary assays, 3 of 13 hits from the HSP70 arm were confirmed. Two of these directly inhibited the intrinsic ATPase activity of HSP90 whereas the third seems to have a different mechanism of action. In the acetylation arm, two compounds increased cellular acetylation, one of which inhibited histone deacetylase activity. A third compound decreased cellular histone acetylation, potentially through a novel mechanism of action..
Sharp, S.Y., Prodromou, C., Boxall, K., Powers, M.V., Holmes, J.L., Box, G., Matthews, T.P., Cheung, K.-., Kalusa, A., James, K., et al.
(2007). Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues. Mol cancer ther,
Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (K(d)) of VER-50589 was 4.5 +/- 2.2 nmol/L compared with 78.0 +/- 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC(50) of 21 +/- 4 nmol/L for VER-50589 compared with 47 +/- 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI(50) values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 +/- 15 and 685 +/- 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and P-glycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI(50) for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors..
Eccles, S.A., Sharp, S.Y., Raynaud, F.I., Valenti, M., Patterson, L., Gowan, S., Boxall, K., Aherne, W., Rowlands, M., Hayes, A., et al.
(2007). NVP-AUY922, a novel diarylisoxazole resorcinol HSP90 inhibitor, potently inhibits growth and metastasis of human tumor xenografts. Mol cancer ther,
Raynaud, F.I., Hayes, A., Martins, V., Smith, N.F., Sharp, S.Y., Valenti, M., Henley, A., Matthews, T.P., Cheung, K.M., Kalusa, A., et al.
(2007). Cassette dosing in tumor bearing animals for the discovery of NVP-AUY922, a novel HSP90 inhibitor. Mol cancer ther,
Hilton, S.T. & Jones, K.
(2007). The tandem radical route to indole alkaloids: an unusual rearrangement reaction. Arkivoc,
Francis, N.J., Rowlands, M., Travers, J., Reynissen, J., Hardcastle, A., Stimson, L., Gamblin, S., Jones, K., Workman, P. & Aherne, W., et al.
(2006). A high throughput screen and secondary assays for the identification and evaluation of histone methyltransferase inhibitors. Ejc suppl,
McDonald, E., Workman, P. & Jones, K.
(2006). Inhibitors of the HSP90 molecular chaperone: attacking the master regulator in cancer. Curr top med chem,
The heat shock protein 90 (HSP90) chaperones represent some 1-2% of all cellular protein and are key players in protein quality control in cells. They are over expressed in many human cancers and the fact that many oncogenic proteins are clients has prompted much recent research on HSP90 inhibitors as new cancer therapeutics. A brief introduction is followed by a detailed review of the various classes of inhibitors, both natural product-based and synthetic, that have emerged over the last decade. The natural products geldanamycin, radicicol and novobiocin have provided the start points for new drugs in this area and their medicinal chemistry is reviewed, including the exciting recent results emerging from clinical trials using geldanamycin analogues. The detailed understanding of the binding mode of these compounds to HSP90 has been significantly enhanced by X-ray crystallography of HSP90 constructs co-crystallised with various ligands. Efforts to replace the natural product inhibitors with more drug-like synthetic compounds have mushroomed over the last 4 years. The purines and the 3,4-diarylpyrazoles have proven to be the most successful and their medicinal chemistry is reviewed with particular emphasis on structure-based design. Protein/ligand co-crystal structures have shown that conserved water molecules in the active site are a vital part of the hydrogen-bonding network established on binding both natural product and synthetic inhibitors. Medicinal chemists have used this information to develop high affinity lead compounds. Recent research provides the platform for exciting developments in the area of HSP90 inhibition over the next few years..
McDonald, E., Jones, K., Brough, P.A., Drysdale, M.J. & Workman, P.
(2006). Discovery and development of pyrazole-scaffold Hsp90 inhibitors. Curr top med chem,
This review explains why the chaperone Hsp90 is an exciting protein target for the discovery of new drugs to treat cancer in the clinic, and summarises the properties of natural product derived inhibitors before relating the discovery and current state of development of synthetic pyrazole compounds. Blockade of Hsp90 results in reduced cellular levels of several proteins implicated in cancer including CDK4, ERBB2 and C-RAF, and causes simultaneous inhibition of cancer cell proliferation in culture and of tumor xenograft growth in vivo. Hsp90 has an ATPase domain that is necessary for its Hsp chaperone function, and X-ray crystallography has shown that natural product inhibitors (geldanamycin, radicicol) of Hsp90 function bind to this domain. High throughput assays focusing on the ATPase activity of Hsp90 were developed and used to discover novel chemical starting points for cancer drug discovery. The discovery, synthesis and SAR of 3,4-diaryl pyrazoles is described. X-Ray crystallography of protein-inhibitor complexes revealed important interactions involving the resorcinol substituent at C-3, and these X-ray structures strongly influenced subsequent medicinal chemistry research that has resulted in highly potent inhibitors with sub-micromolar activity in cells. SAR and X-ray data are summarised for analogues in which the 4-phenyl substituent is replaced by amides or piperazine derivatives. Prospects for the pyrazoles as they progress towards clinical development are discussed in relation to current Phase I trials with derivatives of geldanamycin..
Rossiter, S., Peron, J.M., Whitfield, P.J. & Jones, K.
(2005). Synthesis and anthelmintic properties of arylquinolines with activity against drug-resistant nematodes. Bioorg med chem lett,
2,4-Disubstituted quinolines with additional substituents in positions 5-8 have been found to have anthelmintic properties. A number of 2,4-dimethoxy-6- or 8-arylquinolines have potent activity against the sheep nematode Haemonchus contortus, with LD99 values of the same order of magnitude as levamisole. These arylquinolines maintain their activity against levamisole-, ivermectin- and thiabendazole-resistant strains of H. contortus. (c) 2005 Elsevier Ltd. All rights reserved..
Tyrrell, E., Allen, J., Jones, K. & Beauchet, R.
(2005). Asymmetric 1,3-Dipolar Cycloaddition Reactions of Nitrones with (S)-(-)-4-Benzyl-N-methacryloyl-2-oxazolidinone. Synthesis,
Gravett, E.C., Hilton, P.J., Jones, K. & Peron, J.M.
(2003). A new route to 5-aryl and 5-heteroaryl-2-pyrones via Suzuki coupling of a 2-pyrone-5-boronate ester. Synlett,
Jones, K., Roset, X., Rossiter, S. & Whitfield, P.
(2003). Demethylation of 2,4-dimethoxyquinolines: the synthesis of atanine. Organic & biomolecular chemistry,
Escolano, C. & Jones, K.
(2002). Aryl radical cyclisation onto pyrroles. Tetrahedron,
Escolano, C., Vallverdú, L. & Jones, K.
(2002). Reaction of indolin-2-ones with cerium(IV) ammonium nitrate. Tetrahedron,
Jones, K. & Toutounji, T.
(2001). A short protocol for the synthesis of spirocyclic tetrahydrofurans via intramolecular O–H insertion. Tetrahedron,
Ong, Q., Hameyer, H., Handa, S. & Jones, K.
(2001). Synthetic studies on morphine-based analgesics: an approach to angular substitution in 4a-aryldecahydroisoquinolines via dienolate chemistry. Tetrahedron letters,
Gravett, E.C., Hilton, P.J., Jones, K. & Romero, F.
(2001). A Suzuki coupling approach to bufadienolides. Tetrahedron letters,
Hilton, S.T., Jones, K., Ho, T.C., Pljevaljcic, G. & Schulte, M.
(2001). A tandem radical approach to the ABCE-rings of the Aspidosperma and Strychnos alkaloids. Chemical communications,
Jones, K., Fiumana, A. & Escudero-Hernandez, M.L.
(2000). Pyridine Radicals in Synthesis Part 3: Cyclopentannulation of Pyridine via the 3-Pyridyl Radical and a Formal Synthesis of (±)-Oxerine. Tetrahedron,
Fiumana, A. & Jones, K.
(2000). Annulation of indole via indole radicals: addition of the 2-indolyl radical to aromatic rings. Tetrahedron letters,
Ashraf, M.A., Jones, K. & Handa, S.
(2000). Biomimetic ligands for transition metals: catechol-containing peptides. Bioorganic & medicinal chemistry letters,
Hilton, S.T., Ho, T.C., Pljevaljcic, G. & Jones, K.
(2000). A New Route to Spirooxindoles. Organic letters,
Escolano, C. & Jones, K.
(2000). Aryl radical cyclisation onto pyrroles: a divergent synthesis of spiropyrrolidinyloxindoles and pyrroloquinolines. Tetrahedron letters,
Brunton, S.A. & Jones, K.
(2000). The synthesis of 3-methyleneindol-2(3H )-ones related to mitomycins via 5-exo-dig aryl radical cyclisation. Journal of the chemical society, perkin transactions 1,
Jones, K. & Storey, J.M.
(2000). Intramolecular organolithium addition to indol-2(3H )-ones; an approach to the synthesis of pyrrolo[1,2-a]indoles and pyrido[1,2-a]indoles. Journal of the chemical society, perkin transactions 1,
(1999). Glowing jellyfish, luminescence and a molecule called coelenterazine. Trends in biotechnology,
Jones, K., Brunton, S.A. & Gosain, R.
(1999). The aryl radical route to oxindoles: dependence on temperature and tin hydride concentration. Tetrahedron letters,
Fiumana, A. & Jones, K.
(1999). Intermolecular reactions of indol-2-yl radicals: a new route to 2-substituted indoles. Chemical communications,
Dobbs, A.P., Jones, K. & Veal, K.T.
(1998). Heteroaryl radicals in synthesis: Radical cyclisation reactions of 2-bromoindoles. Tetrahedron,
Jones, K. & Escudero-Hernandez, M.L.
(1998). A short synthesis of (±)-actinidine. Tetrahedron,
Ho, T.C. & Jones, K.
(1997). A synthesis of the tricyclic pyrroloquinoline core of martinelline. Tetrahedron,
Dobbs, A.P., Jones, K. & Veal, K.T.
(1997). Radical cyclisation reactions of 7-bromoindoles. Tetrahedron letters,
Jones, K., Newton, R.F. & Yarnold, C.J.
(1996). Synthetic studies on the ceveratrum alkaloid skeleton. Tetrahedron,
Houghton, P., Osibogun, I., Woldemariam, T. & Jones, K.
(1995). Heteronuclear NMR Studies of the Chromone Alkaloids and Revision of the Structure of Some Piperidino-Chromone Alkaloids. Planta medica,
(1995). Aryl Radical Cyclisation on to a Pyrrole Nucleus. Tetrahedron letters,
Jones, K. & Storey, J.M.
(1993). A route to the pyrrolo[1,2-a]indolenine ring system via intermolecular organolithium addition to an oxindole. Tetrahedron,
Jones, K. & Storey, J.M.
(1993). Aryl radical cyclisation approach to highly substituted oxindoles related to mitomycins. Tetrahedron letters,
Clark, A.J. & Jones, K.
(1992). Cobalt-mediated aryl radical cyclisations: A formal synthesis of physovenine. Tetrahedron,
López-Tudanca, P.L., Jones, K. & Brownbridge, P.
(1991). Substituent control in the synthesis of tetrahydropyrans, oxepanes and oxocanes by episulphonium ion-mediated cyclisation. Tetrahedron letters,
Jones, K. & Woo, K.-.
(1991). A total synthesis of (−)-ruspolinone. Tetrahedron,
Woo, K.-. & Jones, K.
(1991). Asymmetric synthesis from α-amino acids; some reactions of (S)-pyroglutamate. Tetrahedron letters,
Storey, J.M., McCarthy, C. & Jones, K.
(1991). Intramolecular alkyllithium additions to lactams; a synthesis of 2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indoles (pyrrolo[1,2-a]indolemnes) related to mitomycins. Journal of the chemical society, chemical communications,
Jones, K. & Wood, W.W.
(1988). A synthesis of (2S,6S)-2-hydroxymethyl-6-methoxytetrahydropyran; a useful chiral intermediate. Journal of the chemical society, perkin transactions 1,
Wright, C., Shulkind, M., Jones, K. & Thompson, M.
(1987). A formal total synthesis of geneserine. Tetrahedron letters,
Jones, K. & Wood, W.W.
(1986). The preparation and attempted alkylation of some 6-cyano-carbohydrates. Carbohydrate research,
Battersby, A.R., Jones, K. & Snow, R.J.
(1983). Novel Methods for Demetalating Tetrapyrrolic Metallo-Macrocycles. Angewandte chemie international edition in english,
Montforts, F.-., Ofner, S., Rasetti, V., Eschenmoser, A., Woggon, W.-., Jones, K. & Battersby, A.R.
(1979). A Synthetic Approach to the Isobacteriochlorin Macrocycle. Angewandte chemie international edition in english,
Battersby, A.R., Jones, K., McDonald, E., Robinson, J.A. & Morris, H.R.
(1977). The structures and chemistrty of isobacteriochlorins from. Tetrahedron letters,
Robinson, C.W., Rye, C.S., Chessum, N.E. & Jones, K.
A model β-sheet interaction and thermodynamic analysis of β-strand mimetics. Organic & biomolecular chemistry,
Two novel β-strand mimetics are synthesized and their binding to a model peptide is studied in detail by 1H NMR.
Evans, L.E., Cheeseman, M.D., Yahya, N. & Jones, K.
Investigating Apoptozole as a Chemical Probe for HSP70 Inhibition. Plos one,
Rye, C.S., Chessum, N.E., Lamont, S., Pike, K.G., Faulder, P., Demeritt, J., Kemmitt, P., Tucker, J., Zani, L., Cheeseman, M.D., et al.
Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9. Medchemcomm,
A series of 4,6-disubstituted pyrimidines from a phenotypic screen targeting the HSF1 pathway are also potent inhibitors of CDK9.
Rye, C.S., Chessum, N.E., Lamont, S., Pike, K.G., Faulder, P., Demeritt, J., Kemmitt, P., Tucker, J., Zani, L., Cheeseman, M.D., et al.
Correction: Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9 See DOI: 10 1039/c6md00159a. Medchemcomm,
Correction for ‘Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9’ by Carl S. Rye et al., Med. Chem. Commun., 2016, 7, 1580–1586.
Cheeseman, M., Chessum, , Rye, , Pasqua, , Tucker, , Wilding, , Evans, , Richards, , Sharp, , Ali, , et al.
Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen. Journal of medicinal chemistry,
Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than measuring affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug discovery. In this paper, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using an unbiased phenotypic screen to detect inhibitors of the HSF1 stress pathway. The chemical probe is orally bioavailable and displays efficacy in a human ovarian carcinoma xenograft model. By developing cell-based SAR and using chemical proteomics, we identified pirin as a high affinity molecular target, which was confirmed by SPR and crystallography..
Cheeseman, M., Le Bihan, Y., Pettinger, J., Widya, M., van Montfort, R. & Jones, K.
An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56. Angewandte chemie international edition,
The stress-inducible molecular chaperone, HSP72, is an
important therapeutic target in oncology but inhibiting this protein
with small molecules has proven particularly challenging. Validating
HSP72 inhibitors in cells is difficult owing to competition with the high
affinity and abundance of its endogenous nucleotide substrates. We
hypothesized this could be overcome using a cysteine-targeted
irreversible inhibitor. Using rational design, we adapted a validated
8-N-benzyladenosine ligand for covalent bond formation and
confirmed targeted irreversible inhibition. However, no cysteine in
the protein was modified; instead, we demonstrate that lysine-56 is
the key nucleophilic residue. Targeting this lysine could lead to a
new design paradigm for HSP72 chemical probes and drugs..
Cheeseman, M., Evans, L. & Jones, K.
Targeting Secondary Protein Complexes in Drug Discovery: Studying the Druggability and Chemical Biology of the HSP70/BAG1 Complex. Chemical communications,
Proteins typically carry out their biological functions as multi-protein complexes, which can significantly affect the affinity of small-molecule inhibitors. HSP70 is an important target in oncology, so to study its chemical biology and the drug discovery potential of the HSP70/BAG1 complex, we designed a high-affinity non-nucleotide fluorescence polarisation probe..
Cheeseman, M., Pettinger, J. & Jones, K.
Lysine-Targeting Covalent Inhibitors. Angewandte chemie,
Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small molecule/protein crystal structures to design tight-binding ligands with appropriately positioned electrophilic warheads. Whilst most focus has been on targeting binding site cysteine residues, targeting nucleophilic lysine residues can also represent a viable approach to irreversible inhibition. However, owing to the basicity of the ε-amino group in lysine, this strategy generates a number of specific challenges. Herein, we review the key principles for inhibitor design, give historical examples and present recent developments that demonstrate its potential for future drug discovery..
Fok, J.H., Hedayat, S., Zhang, L., Aronson, L.I., Mirabella, F., Pawlyn, C., Bright, M.D., Wardell, C.P., Keats, J.J., de Billy, E., et al.
HSF1: Essential for Myeloma Cell Survival and a Promising Therapeutic Target. Clinical cancer research,
Cheeseman, M., Chessum, N., Sharp, S., Caldwell, J., Pasqua, E., Wilding, B., Colombano, G., Collins, I., Ozer, B., Richards, M., et al.
Demonstrating In-Cell Target Engagement using a Pirin Protein Degradation Probe (CCT367766). Journal of medicinal chemistry,
Demonstrating intracellular protein target engagement is an essential step in the
development and progression of new chemical probes and potential small molecule therapeutics.
However, this can be particularly challenging for poorly studied and non-catalytic proteins, as
robust proximal biomarkers are rarely known. To confirm that our recently discovered chemical
probe 1 (CCT251236) binds the putative transcription factor regulator pirin in living cells, we
developed a heterobifunctional protein degradation probe. Focusing on linker design and
physicochemical properties, we generated a highly active probe 16 (CCT367766) in only three
iterations, validating our efficient strategy for degradation probe design against non-validated
Jones, K. & Wood, W.W.
An approach to the total synthesis of the Prelog–Djerassi lactone. J. chem. soc., perkin trans. 1,
Jones, K., Thompson, M. & Wright, C.
An efficient synthesis of spiro[cyclohexane-1,3′-indol-2′(3′H)-ones]via radical cyclisation. J. chem. soc., chem. commun.,
Handa, S., Jones, K., Newton, C.G. & Williams, D.J.
A short, stereospecific synthesis of a morphine fragment via an intramolecular Diels–Alder reaction. J. chem. soc., chem. commun.,
Handa, S., Jones, K. & Newton, C.G.
An unusual solvent effect in an intramolecular Diels–Alder reaction. J. chem. soc., chem. commun.,
Cheeseman, M., Meyers, J., Chessum, N., Ali, S., Mok, Y., Wilding, B., Pasqua, E., Rowlands, M., Tucker, M., Evans, L., et al.
Privileged Structures and Polypharmacology within and between
Protein Families. Acs medicinal chemistry letters,
Polypharmacology is often a key contributor to the efficacy of a drug, but is also a potential risk. We investigated
two hits discovered via a cell-based phenotypic screen, the CDK9 inhibitor CCT250006 1 and the pirin ligand CCT245232 2, to
establish methodology to elucidate their secondary protein targets. Using computational pocket-based analysis, we discovered intrafamily
polypharmacology for our kinase inhibitor, despite little overall sequence identity. The inter-family polypharmacology of 2
with B-Raf was used to discover a novel pirin ligand from a very small but privileged compound library, despite no apparent ligand
or binding site similarity. Our data demonstrates that in areas of drug discovery where intra-family polypharmacology is often an
issue, ligand dissimilarity cannot necessarily be used to assume different off-target profiles and that understanding inter-family
polypharmacology will be important in the future to reduce the risk of idiopathic toxicity and in the design of screening libraries..