Biomedical subjects

Carol Midgley

Publications and source records attributed to Carol Midgley.

5 recordsLinked to original sources

PubMed2006

Inhibitors of Polo-like kinase reveal roles in spindle-pole maintenance.

Polo-like kinases (Plks) have several functions in mitotic progression and are upregulated in many tumor types. Small-molecule Plk inhibitors would be valuable as tools for studying Plk biology and for developing antitumor agents. Guided by homology modeling of the Plk1 kinase domain, we have discovered a chemical series that shows potent and selective Plk1 inhibition. The effects of one such optimized benzthiazole N-oxide, cyclapolin 1 (1), on purified centrosomes indicate that Plks are required to generate MPM2 epitopes, recruit gamma-tubulin and enable nucleation of microtubules. The compound can also promote loss of centrosome integrity and microtubule nucleating ability apparently through increased accessibility of protein phosphatases. We show that treatment of living S2 cells with cyclapolin 1 leads to collapsed spindles, in contrast to the metaphase-arrested bipolar spindles observed after RNAi. This different response to protein depletion and protein inhibition may have significance in the development of antitumor agents.

Animals↗

PubMed2004

Synthesis and biological activity of 2-anilino-4-(1H-pyrrol-3-yl) pyrimidine CDK inhibitors.

A series of 2-anilino-4-(1H-pyrrol-3-yl)pyrimidines were prepared and evaluated for their ability to inhibit cyclin-dependent kinases (CDKs). A number of analogues were found to be potent CDK2 and CDK4 inhibitors and to exhibit anti-proliferative activity against human tumour cell lines. Structure-activity relationships and biochemical characterization are presented.

Cell Line, Tumor↗

PubMed2004

2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.

Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.

Aniline Compounds↗

PubMed2002

Classroom goal structure and student disruptive behaviour.

BACKGROUND: Achievement goal theory suggests that the emphasis on mastery and performance goals in the classroom (the classroom goal structure) is related to students' patterns of learning and behaviour. This theory can offer a preventative holistic approach for dealing with students' disruptive behaviour. AIMS: The present study investigates whether the goal structure in the classroom is related to the incidence of disruptive behaviour. SAMPLE AND METHODS: A total of 388 ninth-grade students from 60 classrooms in five ethnically diverse high schools responded to surveys asking about the perceived goal structures, their personal achievement goals, and their involvement in disruptive behaviour in their maths classroom. Their maths teachers responded to surveys asking about their goal-related approaches to instruction. RESULTS: Using hierarchical linear modelling (HLM), at the student level, being male and having lower achievement was related to reports of disruptive behaviour. In addition, personal mastery goals were related to lower reports of disruptive behaviour and personal performance-approach and performance-avoidance goals were related to higher reports of disruptive behaviour. Disruptive behaviour also varied significantly between classrooms. Aggregated student perceptions of a mastery goal structure were related to a lower incidence, and aggregated student perceptions of a performance-approach goal structure were related to a higher incidence of disruptive behaviour. CONCLUSION: The implications of the findings to approaches for dealing with disruptive behaviour are discussed.

Adolescent↗

PubMed2001

Academic Self-Handicapping and Achievement Goals: A Further Examination.

This study extends previous research on the relations among students' personal achievement goals, perceptions of the classroom goal structure, and reports of the use of self-handicapping strategies. Surveys, specific to the math domain, were given to 484 7th-grade students in nine middle schools. Personal performance-avoid goals positively predicted handicapping, whereas personal performance-approach goals did not. Personal task goals negatively predicted handicapping. Perceptions of a performance goal structure positively predicted handicapping, and perceptions of a task goal structure negatively predicted handicapping, independent of personal goals. Median splits used to examine multiple goal profiles revealed that students high in performance-avoid goals used handicapping more than did those low in performance-avoid goals regardless of the level of task goals. Students low in performance-avoid goals and high in task goals handicapped less than those low in both goals. Level of performance-approach goals had little effect on the relation between task goals and handicapping. Copyright 2001 Academic Press.

Journal Article↗