Keith Menear

Publications (5)20.61 Total impact

• Article: AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity.

  Christine M Chresta, Barry R Davies, Ian Hickson, Tom Harding, Sabina Cosulich, Susan E Critchlow, John P Vincent, Rebecca Ellston, Darren Jones, Patrizia Sini, [......], Lisa Smith, Sharon Maguire, Marc Hummersone, Karine Malagu, Keith Menear, Richard Jenkins, Matt Jacobsen, Graeme C M Smith, Sylvie Guichard, Martin Pass
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  ABSTRACT: The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, with an IC50 of 0.8 nmol/L. AZD8055 showed excellent selectivity (approximately 1,000-fold) against all class I phosphatidylinositol 3-kinase (PI3K) isoforms and other members of the PI3K-like kinase family. Furthermore, there was no significant activity against a panel of 260 kinases at concentrations up to 10 micromol/L. AZD8055 inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphorylation of the mTORC2 substrate AKT and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 were fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. In vitro, AZD8055 potently inhibits proliferation and induces autophagy in H838 and A549 cells. In vivo, AZD8055 induces a dose-dependent pharmacodynamic effect on phosphorylated S6 and phosphorylated AKT at plasma concentrations leading to tumor growth inhibition. Notably, AZD8055 results in significant growth inhibition and/or regression in xenografts, representing a broad range of human tumor types. AZD8055 is currently in phase I clinical trials.
  Cancer Research 12/2009; 70(1):288-98. · 7.86 Impact Factor
• Source

  Available from: Ian Hickson

  Article: The discovery and optimisation of pyrido[2,3-d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase.

  Karine Malagu, Heather Duggan, Keith Menear, Marc Hummersone, Sylvie Gomez, Christine Bailey, Peter Edwards, Jan Drzewiecki, Frédéric Leroux, Mar Jimenez Quesada, [......], Stephanie Maine, Carrie-Anne Molyneaux, Armelle Le Gall, James Pullen, Ian Hickson, Lisa Smith, Sharon Maguire, Niall Martin, Graeme Smith, Martin Pass
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  ABSTRACT: We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity.
  Bioorganic & medicinal chemistry letters 10/2009; 19(20):5950-3. · 2.65 Impact Factor
• Article: The P1N-isopropyl motif bearing hydroxyethylene dipeptide isostere analogues of aliskiren are in vitro potent inhibitors of the human aspartyl protease renin.

  Yasuchika Yamaguchi, Keith Menear, Nissim-Claude Cohen, Robert Mah, Frédéric Cumin, Christian Schnell, Jeanette M Wood, Jürgen Maibaum
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  ABSTRACT: Novel nonpeptide small molecule renin inhibitors bearing an N-isopropyl P(1) motif were designed based on initial lead structures 1 and aliskiren (2). (P(3)-P(1))-Benzamide derivatives such as 9a and 34, as well as the corresponding P(1) basic tertiary amine derivatives 10 and 35 were found to display low nanomolar inhibition against human renin in vitro.
  Bioorganic & medicinal chemistry letters 09/2009; 19(16):4863-7. · 2.65 Impact Factor
• Article: 8-Biarylchromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK).

  Marine Desage-El Murr, Celine Cano, Bernard T Golding, Ian R Hardcastle, Marc Hummersome, Mark Frigerio, Nicola J Curtin, Keith Menear, Caroline Richardson, Graeme C M Smith, Roger J Griffin
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  ABSTRACT: The synthesis and biological evaluation of libraries of 8-biarylchromen-4-ones enabled the elucidation of structure-activity relationships for inhibition of the DNA-dependent protein kinase (DNA-PK), with 8-(3-(thiophen-2-yl)phenyl)chromen-4-one and 8-(3-(thiophen-3-yl)phenyl)chromen-4-one being especially potent inhibitors.
  Bioorganic & medicinal chemistry letters 10/2008; 18(17):4885-90. · 2.65 Impact Factor
• Article: 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1.

  Keith A Menear, Claire Adcock, Robert Boulter, Xiao-ling Cockcroft, Louise Copsey, Aaron Cranston, Krystyna J Dillon, Jan Drzewiecki, Sheila Garman, Sylvie Gomez, Hashim Javaid, Frank Kerrigan, Charlotte Knights, Alan Lau, Vincent M Loh, Ian T W Matthews, Stephen Moore, Mark J O'Connor, Graeme C M Smith, Niall M B Martin
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  ABSTRACT: Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2 H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.
  Journal of Medicinal Chemistry 10/2008; 51(20):6581-91. · 4.80 Impact Factor