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Instruments / Technical Area	Publication Details	Published
I02-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer Mathieu Unbekandt , Simone Belshaw , Justin Bower , Maeve Clarke , Jacqueline Cordes , Diane Crighton , Daniel R. Croft , Martin J. Drysdale , Mathew J. Garnett , Kathryn Gill , Christopher Gray , David A. Greenhalgh , James A. M. Hall , Jennifer Konczal , Sergio Lilla , Duncan Mcarthur , Patricia Mcconnell , Laura Mcdonald , Lynn Mcgarry , Heather Mckinnon , Carol Mcmenemy , Mokdad Mezna , Nicholas A. Morrice , June Munro , Gregory Naylor , Nicola Rath , Alexander W. Schüttelkopf , Mairi Sime , Michael F. Olson Cancer Research DOI: 10.1158/0008-5472.CAN-17-2870 Diamond Proposal Number(s): [8659] Show Abstract ▼ Abstract: The myotonic dystrophy-related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy.	Jan 2018
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis A. A. Marusiak , N. L. Stephenson , H. Baik , E. W. Trotter , Y. Li , K. Blyth , S. Mason , P. Chapman , L. A. Puto , J. A. Read , C. Brassington , H. K. Pollard , C. Phillips , I. Green , R. Overman , M. Collier , E. Testoni , C. Miller , T. Hunter , O. J. Sansom Cancer Research DOI: 10.1158/0008-5472.CAN-15-0701-T PMID: 26637668 Show Abstract ▼ Abstract: MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers including frequently in colorectal cancer, where their function and pathobiological importance has been uncertain. In this study, we assessed the functional consequences of MLK4 mutations in colon tumorigenesis. Biochemical data indicated that a majority of MLK4 mutations are loss-of-function (LOF) mutations that can exert dominant negative effects. In seeking to understand the abrogated activity of these mutants, we elucidated a new MLK4 catalytic domain structure. To determine whether MLK4 is required to maintain the tumorigenic phenotype, we reconstituted its signaling axis in colon cancer cells harboring MLK4 inactivating mutations. We found that restoring MLK4 activity reduced cell viability, proliferation, and colony formation in vitro and delayed tumor growth in vivo. Mechanistic investigations established that restoring the function of MLK4 selectively induced the JNK pathway and its downstream targets, cJUN, ATF3 and the cyclin-dependent kinase inhibitors CDKN1A and CDKN2B. Our work indicates that MLK4 is a novel tumor suppressing kinase harboring frequent LOF mutations that lead to diminished signaling in the JNK pathway and enhanced proliferation in colon cancer.	Dec 2015
I04-Macromolecular Crystallography	Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy S. Picaud , O. Fedorov , A. Thanasopoulou , K. Leonards , K. Jones , J. Meier , H. Olzscha , O. Monteiro , S. Martin , M. Philpott , A. Tumber , Panagis Filippakopoulos , C. Yapp , C. Wells , K. H. Che , A. Bannister , S. Robson , U. Kumar , N. Parr , K. Lee , D. Lugo , P. Jeffrey , S. Taylor , M. L. Vecellio , C. Bountra , P. E. Brennan , A. O' Mahony , S. Velichko , S. Muller , D. Hay , D. L. Daniels , M. Urh , N. B. La Thangue , T. Kouzarides , R. Prinjha , J. Schwaller , S. Knapp Cancer Research 75, 5106 - 5119 DOI: 10.1158/0008-5472.CAN-15-0236 Diamond Proposal Number(s): [6391] Open Access Show Abstract ▼ Abstract: The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein–protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9+ acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers. Cancer Res; 75(23); 5106–19. ©2015 AACR.	Nov 2015
I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance M. D. Gurden , Isaac Westwood , A. Faisal , S. Naud , K. M. J. Cheung , C. Mcandrew , A. Wood , J. Schmitt , K. Boxall , G. Mak , P. Workman , R. Burke , S. Hoelder , J. Blagg , Rob Van Montfort , S. Linardopoulos Cancer Research 75 (16), 3340 - 3354 DOI: 10.1158/0008-5472.CAN-14-3272 PMID: 26202014 Diamond Proposal Number(s): [8015, 10088] Show Abstract ▼ Abstract: Acquired resistance to therapy is perhaps the greatest challenge to effective clinical management of cancer. With several inhibitors of the mitotic checkpoint kinase MPS1 in preclinical development, we sought to investigate how resistance against these inhibitors may arise so that mitigation or bypass strategies could be addressed as early as possible. Toward this end, we modeled acquired resistance to the MPS1 inhibitors AZ3146, NMS-P715, and CCT251455, identifying five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed how the MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. Notably, we show that these mutations occur in nontreated cancer cell lines and primary tumor specimens, and that they also preexist in normal lymphoblast and breast tissues. In a parallel piece of work, we also show that the EGFR p.T790M mutation, the most common mutation conferring resistance to the EGFR inhibitor gefitinib, also preexists in cancer cells and normal tissue. Our results therefore suggest that mutations conferring resistance to targeted therapy occur naturally in normal and malignant cells and these mutations do not arise as a result of the increased mutagenic plasticity of cancer cells.	Aug 2015
I04-Macromolecular Crystallography	PFI-1, a Highly Selective Protein Interaction Inhibitor, Targeting BET Bromodomains S. Picaud , D. Da Costa , A. Thanasopoulou , P. Filippakopoulos , P. V. Fish , M. Philpott , O. Fedorov , P. Brennan , M. E. Bunnage , D. R. Owen , J. E. Bradner , P. Taniere , B. O'Sullivan , S. Muller , J. Schwaller , T. Stankovic , S. Knapp Cancer Research 73 (11), 3336 - 3346 DOI: 10.1158/0008-5472.CAN-12-3292 PMID: 23576556 Diamond Proposal Number(s): [8421] Show Abstract ▼ Abstract: Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression.	May 2013
B22-Multimode InfraRed imaging And Microspectroscopy	Infrared spectroscopy and microscopy in cancer research and diagnosis Giuseppe Bellisola , Claudio Sorio American Journal Of Cancer Research 2 (1)	Nov 2011
I03-Macromolecular Crystallography	CCT241533 Is a Potent and Selective Inhibitor of CHK2 that Potentiates the Cytotoxicity of PARP Inhibitors Victoria E. Anderson , M. I. Walton , P. D. Eve , Kathy Boxall , L. Antoni , J. J. Caldwell , W. Aherne , L. H. Pearl , Antony W. Oliver , I. Collins , M. D. Garrett Cancer Research 71 (2), 463 - 472 DOI: 10.1158/0008-5472.CAN-10-1252 PMID: 21239475 Diamond Proposal Number(s): [6385] Show Abstract ▼ Abstract: CHK2 is a checkpoint kinase involved in the ATM-mediated response to double-strand DNA breaks. Its potential as a drug target is still unclear, but inhibitors of CHK2 may increase the efficacy of genotoxic cancer therapies in a p53 mutant background by eliminating one of the checkpoints or DNA repair pathways contributing to cellular resistance. We report here the identification and characterization of a novel CHK2 kinase inhibitor, CCT241533. X-ray crystallography confirmed that CCT241533 bound to CHK2 in the ATP pocket. This compound inhibits CHK2 with an IC50 of 3 nmol/L and shows minimal cross-reactivity against a panel of kinases at 1 mu mol/L. CCT241533 blocked CHK2 activity in human tumor cell lines in response to DNA damage, as shown by inhibition of CHK2 autophosphorylation at S516, band shift mobility changes, and HDMX degradation. CCT241533 did not potentiate the cytotoxicity of a selection of genotoxic agents in several cell lines. However, this compound significantly potentiates the cytotoxicity of two structurally distinct PARP inhibitors. Clear induction of the pS516 CHK2 signal was seen with a PARP inhibitor alone, and this activation was abolished by CCT241533, implying that the potentiation of PARP inhibitor cell killing by CCT241533 was due to inhibition of CHK2. Consequently, our findings imply that CHK2 inhibitors may exert therapeutic activity in combination with PARP inhibitors. Cancer Res; 71(2); 463-72. (C) 2011 AACR.	Jan 2011

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