Thesis

Developing chemical tools for the cancer kinome, targeting DYRK2 in triple negative breast cancer

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2020
Thesis identifier
  • T15823
Person Identifier (Local)
  • 201673989
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Protein kinases are one of the largest protein families in the human genome under investigation as therapeutic targets for their involvement in cancer. Their role, phosphorylation, is an essential post-translational modification required for normal function. DYRK2 (Dual-Specificity Tyrosine(Y) Regulated Kinase-2) has been reported to play a promiscuous role in cancer. However, research has revealed that DYRK2 plays an important role in activating the proteasome. In addition, in vivo studies have shown that DYRK2 inhibition impedes tumour growth in Triple Negative Breast Cancer (TNBC) mice xenografts. Thus, we were particularly interested in validating DYRK2 as a target for the treatment of TNBC. TNBC is an aggressive, heterogeneous disease and accounts for 10–20% of breast cancer related deaths in women. It is named due to its lack of three key receptors (ER, PR and HER2) and as a result the current treatment options, chemotherapy, surgery and radiotherapy are also aggressive in nature. Thus, there is a clinical demand for the identification of alternative biological targets for TNBC therapy. Through collaboration with Professor Joanne Edwards at the University of Glasgow and Dr Laureano de la Vega at the University of Dundee, we have reinforced the synergistic relationship between DYRK2 and TNBC. We discovered that DYRK2 expression negatively affects TNBC patient survival and is essential for cancer cell growth via the phosphorylation of Heat Shock Factor-1 (HSF1), the master regulator of proteotoxic stress pathways. This work allowed us to expand upon the SAR of DYRK2 inhibitors and discover a DYRK2 inhibitor, 68 with >10-fold increase in potency compared to the previous lead CI709 (68 Ki 19 nM). Pleasingly, 68 is selective for DYRK2 against its closely related isoform DYRK1A (IC50 >10 μM) in vitro. 68 and closely related analogue CI709 were tested in TNBC cell models and have been shown to impede cancer cell growth in the MDA-MB-468 cell line. In addition, 68 and CI709 inhibit the phosphorylation of HSF1 at two significant sites, Ser320 and Ser326, in TNBC cells. These findings strengthen the reasons for the validation of DYRK2 as a target for investigation in TNBC treatment.
Advisor / supervisor
  • MacKay, Simon
  • Tomkinson, Nick
Resource Type
Note
  • This thesis was previously held under moratorium from 31/03/2021 until 31/03/2024. Access to the digital copy is restricted to Strathclyde users until 31/03/2026.
DOI
Date Created
  • 2020
Former identifier
  • 9912970192502996
Embargo Note
  • This thesis is restricted to Strathclyde users only until 31 March 2026.

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