Structure-guided approaches to the design of novel autotaxin inhibitors

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2016
Thesis identifier
  • T14666
Person Identifier (Local)
  • 201384935
Qualification Level
Qualification Name
Department, School or Faculty
  • Autotaxin (ATX) is a secreted enzyme responsible for the production and subsequent delivery of lysophosphatidic acid (LPA) to G-protein coupled receptors (GPCR) LPA1-6. LPA binds at LPA1 to induce downstream signaling effects such as migration, proliferation and survival of cells. The ATX-LPA signaling pathway is implicated in a vast number of conditions such as; idiopathic pulmonary fibrosis, cancer, angiogenesis, osteoarthritis, and cardiovascular diseases. ATX consists of an active site containing two zinc atoms adjacent to a large hydrophobic pocket. The active site is solvent accessible via a hydrophobic tunnel unique to this family of enzymes. Reported ATX inhibitors contain common pharmacophores consisting of a zinc binding ‘warhead’ and a lipophilic region, which reside in the active site and hydrophobic pocket respectively. This is best exemplified by PF-8380, a known ATX inhibitor (IC50 = 2.8 nM, Figure 1). This thesis will explore the development of a structure-activity relationship (SAR) of tool compound PF-8380, resulting in a highly potent hit compound containing a novel diamine core. Within this emerging series, we sought to tune key physicochemical parameters whilst maintaining potency at ATX. The lead series focused on compounds containing this diamine core in combination with novel zinc binders. Resulting compounds were tested in BJEH fibroblast cell lines, showing a significant inhibitory effect on downstream signaling (Figure 1). Figure 1 Development of PF-8380 SAR [see thesis for image]. In a related study, analysis of the apo form of ATX showed the presence of ‘ghost’ electron density in the tunnel region. This density was resolved as a bile salt, which was residing in the hydrophobic tunnel of ATX (UDCA IC50 = 8.8 µM). Merging this information with the SAR landscape described above, we developed a structure based design approach of hybrid UDCAPF compounds, utilizing this endogenous modulator of ATX. Hybrid compounds span both the tunnel and hydrophobic pocket of ATX, resulting in highly potent steroid-PF analogues. The binding mode hypothesis was confirmed by co-crystallographic data bound to ATX, and a kinetic study. Additionally, compounds also exhibited significant cell based activity and promising in vivo results (Figure 2). Figure 2 Co-crystallographic data leading to structure-based design of UDCA-PF hybrid inhibitors [see thesis for image].
Advisor / supervisor
  • Jamieson, Craig
  • Watson, Allan
Resource Type
  • Previously held under moratorium from 21st August 2017 until 21st August 2022.
Date Created
  • 2016
Former identifier
  • 9912559577602996