Investigation and application of 3-Oxabicyclo[4.1.0]heptane as a mechanistic target of rapamycin (mTOR) kinase hinge binding fragment

  • Declan Mathew Summers

Student thesis: Doctoral Thesis

Abstract

The modulation of kinase activity for treatment of diseases has gained increased attention over the last 20 years and drugs targeting kinases have been developed for a range of diseases including cancers,1-3 inflammatory diseases,4,5 central nervous system disorders,6 cardiovascular diseases and complications related to diabetes.7 Recently, this attractive class of targets have been investigated for treatment of Idiopathic Pulmonary Fibrosis (IPF), a progressive and fatal lung disease which causes 40,000 deaths per year in the USA8 and is an increasingly prominent problem within our ageing society. This thesis presents scientific research towards the identification of small molecule therapies for Idiopathic Pulmonary Fibrosis through targeting a lipid kinase pathway. Chapter 1 concerns a theoretical and experimental investigation into 3-oxabicyclo[4.1.0]heptane (cyclopropylpyran) which has recently been identified as a novel hinge binding fragment for mechanistic target of rapamycin (mTOR) and related lipid kinases, whilst chapter 2 concerns the application of this 3-oxabicyclo[4.1.0]heptane hinge binding fragment to a series of pyrazolopyrimidine based mTOR inhibitor compounds. The research aims were firstly to investigate the scope of 3-oxabicyclo[4.1.0]heptane as a kinase hinge binding fragment. To do this a range of computational, crystallographic and spectroscopic experiments have been used to investigate the conformational preferences of a range of 3-oxabicyclo[4.1.0]heptane containing tool compounds. Subsequently, knowledge gained in chapter 1 was applied to the development of a series of mTOR inhibitor compounds based on a pyrazolopyrimidine core. This work focused on identifying highly active compounds with appropriate physicochemical profiles which have the potential to progress further into pharmacokinetic studies. The results presented in this thesis demonstrate significant advancements towards these goals, and offer encouragement that an improved standard of care for IPF is possible.
Date of Award25 Apr 2019
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde
SupervisorCraig Jamieson (Supervisor) & William Kerr (Supervisor)

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