Design and Development of Reversible Inhibitors of Lysine Specific Demethylase 1

  • Daniel Mould

Student thesis: Phd

Abstract

Lysine specific demethylase 1 is an epigenetic modulator that has been shown to have complex and wide-ranging roles in maintaining the balance between stem-cells and differentiated cells in a number of cell-types. From the output of a high-throughput screen of 150,000 compounds, we remade the most promising hits and conducted initial library synthesis to develop initial structure activity relationships. After this initial synthetic effort, we chose to develop a series of sulfonamides that looked to have scope for diversification and fully explored the SAR, achieving a 100-fold increase in potency over the initial hit. Despite the initial promise, we were not able to achieve cellular activity with this series. This disconnect was explained when this series, as well as several others from the HTS, were found to display no specific binding to the LSD1 protein by surface plasmon resonance. To generate novel series of reversible inhibitors, we chose to develop an existing literature reversible inhibitor, GSK-690, by using in silico design and rational medicinal chemistry to develop potential scaffold-hops. We found that acyclic scaffolds can be developed that retain similar levels of activity against the parent compound by SPR and in cellular assays. In addition, these compounds lack the hERG liability that precluded development of the parent compound. Additionally, we looked to exploit the developing patent literature, by targeting underdeveloped series that had been disclosed, but not claimed, and showed promising levels of activity against LSD1. A series of 5-hydroxypyrazoles was exemplified by optimising the ether functionality and we achieved a 10-fold increase in potency over the compound disclosed in the patent literature. With Kd values of
Date of Award1 Aug 2018
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorAllan Jordan (Supervisor) & Ian Waddell (Supervisor)

Keywords

  • drug discovery
  • acute myeloid leukaemia
  • scaffold-hopping
  • Lysine specific demethylase 1
  • cancer
  • leukaemia
  • organic chemistry
  • medicinal chemistry
  • epigenetics

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