Tang, Jiazhi;
(2022)
Structural and functional studies of the human mitotic kinesins MPP1 and KifC1, kinase DYRK2, and antibody A33 Fab and their potential as targets for development of cancer chemotherapy drugs.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The work described in this thesis focuses on the early-phase development of anti-cancer treatments based on small therapeutic molecules and therapeutic antibodies, which target key factors, including Kinesin Family Member C1 (KifC1), M-Phase Phosphoprotein 1 (MPP1), Dual Specificity Tyrosine Phosphorylation Regulated Kinase 2 (DYRK2), and human glycoprotein A33 antigen, during the formation and development of cancer. The first part of the thesis covers investigation of two human mitotic kinesins, KifC1 (also called human spleen, embryo and testes protein, HSET; kinesin-14 family) and MPP1 (kineisn-6 family), which are pivotal in cell division, with an emphasis on early-phase fragment-based drug discovery. Several small-molecule hits were identified and characterised using various assays. Attempts for acquiring the protein crystals of these kinesins are also described. The second part of the thesis describes the crystallisation and structure determination of a well-developed immunotherapy molecule, human A33 Fab, which targets a key factor during colorectal cancer development. Protein crystals of the human A33 Fab were obtained, and the structure of A33 Fab was determined. A comprehensive analysis of A33 Fab structure was conducted, which formed the basis of research conducted by our collaboration partners. The last part of the thesis covers a mechanistic investigation of selective inhibitors of human DYRK2, a cancer-related kinase. DYRK2 plays a pivotal role in the development of triple-negative breast cancer (TNBC). The crystal structures of DYRK2 in complex with three distinct inhibitors were determined. Ligand-protein interactions were analysed to explain the affinity and selectivity of the inhibitors, which may provide guidance for further drug development.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Structural and functional studies of the human mitotic kinesins MPP1 and KifC1, kinase DYRK2, and antibody A33 Fab and their potential as targets for development of cancer chemotherapy drugs |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10158730 |
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