Fragment-based screening of the oncogenic protein tyrosine phosphatase SHP2

Quill, Lee Daniel (2017). Fragment-based screening of the oncogenic protein tyrosine phosphatase SHP2. University of Birmingham. Ph.D.

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Abstract

Protein tyrosine phosphatases represent a family of signalling enzymes with emerging therapeutic potential. The cytoplasmic protein tyrosine phosphatase SHP2, encoded by the PTPN11 gene, plays a central role in the activation of downstream signalling events at multiple growth factor and cytokine receptors, and was the first oncogenic protein tyrosine phosphatase to be discovered. Aberrant SHP2 signalling underlies the pathology of numerous developmental disorders such as Noonan and LEOPARD syndrome, and is a known driver of breast cancer and myeloproliferative disease. To gain a deeper insight into ligand interactions with the SHP2 catalytic domain in solution, NMR backbone resonance assignments of the 34 KDa SHP2 catalytic domain were determined and utilised in conjunction with 15N-1H HSQC NMR spectroscopy to map the structurally undisclosed binding site of the previously reported SHP2 inhibitor, NSC-87877. In addition, use of a fragment-based screening approach to accelerate the discovery of novel SHP2 inhibitors has enabled the identification of two novel and distinct chemical scaffolds, both of which now serve as validated chemical precursors for the development of more potent SHP2 lead inhibitors.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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