Atropisomeric fragments in drug discovery and probe compound development

Thesis

This thesis describes work on the use of atropisomeric biaryl compounds in fragment-based drug discovery (FBDD) and probe compound development.

Part I describes the investigation of derivatisation methodologies and fragment growth methodologies to generate axially chiral biarylpyrimidines with high rotational barriers, for potential incorporation in FBDD screening libraries. We explored 6 derivatisation methodologies, yielding 23 examples. When carried out on enantioenriched substrates, conservation of the enantiomeric ratio was observed and the compounds displayed high enantiomeric stability in most cases (ΔG > 30 kcal/mol).

Part II describes the exploitation of axially chiral biarylpyrimidine fragments to synthesise molecular probes for KRas G12C covalent inhibition, following the discovery of sotorasib (AMG 510). Probe 120 was synthesised, assessed in biological studies, and optimised to lead to probe 150, active against KRas G12C in the low micromolar range as a racemate.

Authors: Danet, B

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Fragment Based Drug Discovery; Synthesis; Atropisomerism
• Subjects: Pharmaceutical Chemistry; Medicinal Chemistry; Drug Discovery