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Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response
TLDR
The studies identify human Ire1α as a target for development of ATP‐competitive inhibitors that will modulate the UPR in human cells, which has particular relevance for myeloma and other secretory malignancies.
A Phase I Study of the Heat Shock Protein 90 Inhibitor Alvespimycin (17-DMAG) Given Intravenously to Patients with Advanced Solid Tumors
TLDR
The maximum tolerated dose (MTD) was the highest dose at which ≤1/6 patients experienced dose limiting toxicity (DLT) and the recommended phase II dose of 17-DMAG is 80 mg/m2 weekly i.v.
Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues
TLDR
The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors as well as the superiority of VER-50589 over VER-49009.
High-throughput screening for identification of small molecule inhibitors of histone acetyltransferases using scintillating microplates (FlashPlate).
TLDR
A microplate assay for HAT activity suitable for high-throughput screening and showing that a signal was effectively produced by histone passively binding to the walls of the FlashPlate resulted in a simple "mix and measure" assay that is currently being used for the identification of HAT inhibitors.
Application of meso scale technology for the measurement of phosphoproteins in human tumor xenografts.
TLDR
A rapid screen to monitor PD responses within xenografted human tumors as an important step towards a clinically applicable technology is developed and optimized of the Meso Scale Discovery (MSD) platform.
Determinants of cytotoxicity with prolonged exposure to fluorouracil in human colon cancer cells.
TLDR
The gradual and stable accumulation of FUra in RNA noted in both lines may account for the thymidine-insensitive component of F Ura toxicity, and the interference with nascent DNA chain elongation and induction of single-strand breaks in newly synthesized DNA in both cell lines may be due to misincorporation of deoxyuridine nucleotides.
Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines.
TLDR
Four cell lines, the mouse L1210 leukaemia, the human W1L2 lymphoblastoid and two human ovarian cells, were made resistant to ZD1694 by continual exposure to incremental doses of the drug by finding cross-resistance was found to those compounds known to be active through polyglutamation.
Thymidylate synthase expression in advanced colorectal cancer predicts for response to raltitrexed.
TLDR
High TS mRNA expression predicts nonresponse to RTX and limited genomic fingerprinting could optimize single-agent therapy, allowing combinations to be reserved for high TS-expressing patients or for treatment failures, with potential reductions in toxicity and cost.
A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points
TLDR
Clinical experience showed that patients who had breaks of therapy longer than a week could not have treatment reinitiated at a dose of 190 mg m−2 without unacceptable toxicity, thus the 145‬mg‬m− 2 dose level is the recommended dose for future study.
Antitumour evaluation of dolastatins 10 and 15 and their measurement in plasma by radioimmunoassay
TLDR
The highly sensitive RIA will be useful for pharmacokinetic studies in conjunction with the planned phase I clinical trials of these novel, extremely potent, tubulin-binding agents, of which dolastatin 10 appears to possess the more promising preclinical features.
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