A5071262153- RNA and protein synthesis mechanisms
- Tuberculosis Research and Epidemiology
- Advanced Breast Cancer Therapies
- Cancer-related Molecular Pathways
- RNA regulation and disease
- Education, Psychology, and Social Research
- RNA Research and Splicing
- Biochemical and Molecular Research
- Chronic Lymphocytic Leukemia Research
- Fungal and yeast genetics research
- Cancer therapeutics and mechanisms
- Microtubule and mitosis dynamics
- Cancer Mechanisms and Therapy
- Mycobacterium research and diagnosis
- Bacteriophages and microbial interactions
- Acute Myeloid Leukemia Research
- Pneumocystis jirovecii pneumonia detection and treatment
- HER2/EGFR in Cancer Research
- Computational Drug Discovery Methods
- RNA modifications and cancer
- Protein Degradation and Inhibitors
- Diagnosis and treatment of tuberculosis
- Peptidase Inhibition and Analysis
- Multiple Myeloma Research and Treatments
- Viral Infections and Immunology Research
University of Dundee
2016-2025
Cyclacel Pharmaceuticals (United Kingdom)
2005-2023
Wellcome Centre for Anti-Infectives Research
2022-2023
Harvard University
2022
Glasgow School of Art
2019
University of Glasgow
2019
Harlow College
2014
Dartmouth–Hitchcock Medical Center
2009
Massachusetts General Hospital
2009
The University of Texas MD Anderson Cancer Center
2009
The interferon-induced protein kinase DAI, the double-stranded RNA (dsRNA)-activated inhibitor of translation, plays a key role in regulating synthesis higher cells. Once activated, process that involves autophosphorylation, it phosphorylates initiation factor eIF-2, leading to inhibition polypeptide chain initiation. activity DAI is controlled by regulators, including dsRNA activators and highly structured single-stranded RNAs which block activation dsRNA. To elucidate mechanism activation,...
Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant cells chronic exposure to treatment. Genomewide copy-number variation analyses the resistant compared parental revealed a focal amplification genomic DNA containing cyclin E gene. In cohort 34 + treated trastuzumab-based therapy, found that...
has an unusual outer membrane that lacks canonical porin proteins for the transport of small solutes to periplasm. We discovered 3,3-
Seliciclib (CYC202, R-roscovitine) is a cyclin-dependent kinase (CDK) inhibitor that competes for the ATP binding site on kinase. It has greatest activity against CDK2/cyclin E, CDK7/cyclin H, and CDK9/cyclin T. induces apoptosis from all phases of cell cycle in tumor lines, reduces growth xenografts nude mice currently phase II clinical trials. This study investigated mechanism death multiple myeloma cells treated with seliciclib. In vitro, seliciclib induced rapid dephosphorylation...
S R Green and M B Mathews Cold Spring Harbor Laboratory, New York 11724.
Abstract Cyclin-dependent kinase (CDK) inhibitors have the potential to induce cell-cycle arrest and apoptosis in cancer cells. Seliciclib (CYC202 or R-roscovitine) is a potent CDK inhibitor currently undergoing phase-2 clinical testing lung B-cell malignancies. Here we studied vitro cytotoxic activity of seliciclib against multiple myeloma (MM) Our data demonstrate that has cytotoxicity MM cells are both sensitive resistant conventional therapy as well primary from patients. Cell-cycle...
The yeast two-hybrid system and far-Western protein blot analysis were used to demonstrate dimerization of human double-stranded RNA (dsRNA)-dependent kinase (PKR) in vivo vitro. A catalytically inactive mutant PKR with a single amino acid substitution (K296R) was found dimerize vivo, deletion the catalytic domain retained ability dimerize. In contrast, two dsRNA-binding motifs N-terminal regulatory abolished dimerization. vitro required presence dsRNA. These results suggest that binding...
The interferon-induced protein kinase DAI, the double-stranded RNA (dsRNA)-activated inhibitor of translation, plays a key role in regulating synthesis higher cells. Once activated, process that involves autophosphorylation, it phosphorylates initiation factor eIF-2, leading to inhibition polypeptide chain initiation. activity DAI is controlled by regulators, including dsRNA activators and highly structured single-stranded RNAs which block activation dsRNA. To elucidate mechanism activation,...
A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This compound did not directly inhibit cell wall biogenesis but triggered a slow lysis Mtb cells as measured release intracellular green fluorescent protein (GFP). Isolation resistant mutants followed whole-genome sequencing showed an unusual gene amplification 40 region spanning from Rv3371 to Rv3411c and in one case...
Mycobacterium tuberculosis (MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing structure-based design small-molecule inhibitors. Herein, we disclose MTb whole-cell structure–activity relationships (SARs) series 2-mercapto-quinazolinones target ndh encoded with nanomolar potencies. The...
ABSTRACT The recent development and use of protease inhibitors have demonstrated the essential role that combination therapy will play in treatment individuals infected with human immunodeficiency virus type 1 (HIV-1). Past clinical experience suggests due to appearance resistant HIV-1 variants, additional therapeutics be required future. To identify new options for therapy, it is paramount importance pursue novel targets drug development. Ribosomal frameshifting one potential target has not...
AbstractThe protein kinase DAI is activated upon viral infection of mammalian cells and inhibits synthesis by phosphorylation the α subunit translation initiation factor 2 (eIF-2α). in vitro double-stranded RNAs (dsRNAs), binding dsRNA dependent on two copies a conserved sequence motif located N terminal to domain DAI. High-level expression Saccharomyces cerevisiae lethal because hyperphosphorylation eIF-2α; at lower levels, can functionally replace GCN2 stimulate GCN4 mRNA. These phenotypes...
The RNA-binding domain of the protein kinase DAI, double-stranded RNA inhibitor translation, contains two repeats a motif that is also found in number other proteins. This consists 67 amino acid residues and predicted to contain positively charged α helix at its C terminus. We have analyzed effects equivalent single changes three conserved distributed over each copy motif. Mutants C-terminal portion either repeat were severely defective, indicating both copies are essential for binding....
With the emergence of multidrug-resistant strains Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms action. Herein, we describe identification morpholino-thiophenes (MOT) series following phenotypic screening Eli Lilly corporate library against M. strain H37Rv. The design, synthesis, and structure-activity relationships range analogues around confirmed actives are described. Optimized leads potent whole cell activity H37Rv, no cytotoxicity flags, in...
Sapacitabine is an oral deoxycytidine nucleoside analog with a unique mechanism of action that different from cytarabine.To define the dose-limiting toxicities (DLT) and maximum-tolerated dose (MTD) sapacitabine given orally twice daily for 7 days every 3 to 4 weeks, or 2 weeks (days 1 through 8 10) in refractory-relapse acute leukemia myelodysplastic syndrome (MDS). A total 47 patients were treated phase I study used classical + design. was escalated 75 375 mg (n = 35) 475 on 10.The DLTs...
Abstract Purpose: Cyclin-dependent kinases (Cdk) and their associated cyclins are targets for lung cancer therapy chemoprevention given frequent deregulation in carcinogenesis. This study uncovered previously unrecognized consequences of targeting the cyclin E–Cdk-2 complex cancer. Experimental Design: Cyclin E, Cdk-1, Cdk-2 were individually targeted repression with siRNAs cell lines. was also pharmacologically inhibited reversible kinase inhibitor seliciclib. Potential reversibility...
With the emergence of multi-drug-resistant strains Mycobacterium tuberculosis, there is a pressing need for new oral drugs with novel mechanisms action. A number scaffolds potent anti-tubercular in vitro activity have been identified from phenotypic screening that appear to target MmpL3. However, are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic amines cytotoxic against mammalian cell lines...
Abstract Tuberculosis is a major global cause of both mortality and financial burden mainly in low middle-income countries. Given the significant ongoing rise drug-resistant strains Mycobacterium tuberculosis within clinical setting, there an urgent need for development new, safe effective treatments. Here drug-like series based on fused dihydropyrrolidino-pyrimidine scaffold described. The has been developed against M. lysyl-tRNA synthetase (LysRS) cellular studies support this mechanism...
Although not currently in the infectious disease spotlight, there is still a pressing need for new agents to treat tuberculosis caused by Mycobacterium tuberculosis. As an ever-increasing amount of clinical resistance current drugs, ideally drugs would be found against novel targets circumvent pre-existing resistance. A phenotypic growth screen identified singleton, 1, as inhibitor M. growth. Mechanism-of-action studies determined that 1 targeted Pks13, essential enzyme cell wall...
The Tat-responsive region (TAR) sequence is present at the 5' end of human immunodeficiency virus 1 mRNAs and as a cytoplasmic form 58-66 nucleotides. TAR RNA blocks activation autophosphorylation double-stranded RNA-activated protein kinase in vitro. We show here that also prevents RNA-mediated inhibition translation cell-free system. Mutagenic structural analyses indicate stem least 14 base pairs required for this activity, whereas loop bulge transactivation by Tat are dispensable....
ABSTRACT We have examined the cellular distribution of double-stranded RNA-activated protein kinase DAI in adenovirus 2 (Ad2) -infected and uninfected HeLa cells. In cells was found to be concentrated cytoplasm. addition, localized nucleoli diffusely distributed throughout nucleoplasm. Cells treated with α-interferon displayed a similar pattern for DAI. When RNA polymerase I activity inhibited by drug actinomycin D, segregated colocalize dense fibrillar region nucleoli. During mitosis,...
With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, agents should work through novel targets so that they are unencumbered by preexisting clinical to current treatments. Benzofuran 1 was identified as a potential lead TB inhibiting target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability inhibition hERG cardiac ion channel. This article describes...