Thesis

Structure-guided discovery of a novel steroid-derived family of autotaxin inhibitors based on endogenous allosteric modulators

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2021
Thesis identifier
  • T15920
Person Identifier (Local)
  • 201650058
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Autotaxin (ATX) facilitates the hydrolysis of lysophosphatidyl choline to lysophosphatidic acid, a bioactive signalling lipid, which acts on its cognate receptors to facilitate a diverse range of cellular effects in multiple tissues. Abnormal LPA expression can lead to the progression of diseases such as cancer and fibrosis. Modulation of ATX has been predominantly based around the generation of orthosteric or “Type I” inhibitors, which structurally mimic the natural substrate, LPA (Figure 1). However, despite being active, their therapeutic development has been limited. Progress in inhibitor diversification has recently led to the evolution of potent hybrid inhibitors binding in both the tunnel and pocket of ATX, which fall into the class of “Type IV” inhibitors. Collaboration between Netherlands Cancer Institute and University of Strathclyde has facilitated the development of a novel class of inhibitors which can be confidently designated as first-in-class “Type V” inhibitors (Figure 2), the design, synthesis and biological evaluation of which will be described in this thesis. Amalgamation of key structural features from two comprehensive historical design hypotheses, based on both endogenous allosteric modulators and competitive orthosteric inhibitors, has led to the discovery of steroid-derived inhibitors armed with a key warhead pharmacophore, capable of interacting with the tunnel and active site of ATX. Our binding hypothesis has been corroborated with three crystallographic structures of potent exemplar compounds bound to ATX, one of which we additionally disclose as a novel zinc binder with comparable potency to our lead analogue. Further confirmatory studies have been undertaken through ATX kinetics, cell-based analysis and phenotypic studies in order to ascertain the fate of these novel compounds in the downstream signalling cascade and also in a disease-relevant context. Our lead compounds act through competitive inhibition of ATX and achieve modulation of LPA mediated ATX allostery and inhibition of LPA-dependent signalling pathways in cells, which we believe serves as a solid baseline for further investigation into the impact of ATX in debilitating diseases, such as fibrosis and cancer (Figure 3). [See thesis pp. v-vii for figures]
Advisor / supervisor
  • Jamieson, Craig.
Resource Type
Note
  • Error on title page - year of award is 2021
DOI
Date Created
  • 2020
Embargo Note
  • This thesis is restricted to Strathclyde users only until 1st August 2026.

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