Towards the design and synthesis of small molecule antagonists of nuclear receptor liver receptor homologue-1
Author(s)
Rey, Jullien
Type
Thesis
Abstract
Nuclear receptors (NRs) are a large family of mammalian transcription factors that
have the particularity of binding directly to DNA and regulating the expression of
adjacent genes. Liver receptor homologue-1 (LRH-1) is a NR from the subfamily 5
(steroidogenic factor-like) and plays a prominent role in development, reverse
cholesterol transport, bile-acid homeostasis and steroidogenesis, as well as being
implicated in the control of aromatase expression. In addition, Ali et al. showed that
LRH-1 acts as a key regulator of the estrogen response in breast cancer cells through
the regulation of estrogen receptor-α (ERα) expression.
As a crystal structure of LRH-1 was available, the design of new potential LRH-1
antagonists was based on a computer-aided drug design (CADD) approach. It was
believed that virtual agonist and antagonist analogues would bind at the same site
within the core of the ligand-binding domain (LBD) but demonstrate different binding
modes. Binding of an antagonist would induce a conformational change within the
LBD of LRH-1, involving a rotation of helix 12 (H12) by direct steric clashes between
this helix and the ligand and as a consequence, prevent co-activator recruitment. The
LRH-1 LBD was identified as mainly hydrophobic and as one of the largest in the NR
family. Three series of analogues have been designed. Steroid-based compounds
bearing a challenging C-2 ether linkage were initially synthesized followed by
analogues structurally related to anti-estrogen agents tamoxifen and
raloxifene (Scheme 0).
[diagram included in print copy, unable to reproduce electronically]
Scheme 0 – Three series of virtual LRH-1 antagonists from our CADD approach [diagram label]
have the particularity of binding directly to DNA and regulating the expression of
adjacent genes. Liver receptor homologue-1 (LRH-1) is a NR from the subfamily 5
(steroidogenic factor-like) and plays a prominent role in development, reverse
cholesterol transport, bile-acid homeostasis and steroidogenesis, as well as being
implicated in the control of aromatase expression. In addition, Ali et al. showed that
LRH-1 acts as a key regulator of the estrogen response in breast cancer cells through
the regulation of estrogen receptor-α (ERα) expression.
As a crystal structure of LRH-1 was available, the design of new potential LRH-1
antagonists was based on a computer-aided drug design (CADD) approach. It was
believed that virtual agonist and antagonist analogues would bind at the same site
within the core of the ligand-binding domain (LBD) but demonstrate different binding
modes. Binding of an antagonist would induce a conformational change within the
LBD of LRH-1, involving a rotation of helix 12 (H12) by direct steric clashes between
this helix and the ligand and as a consequence, prevent co-activator recruitment. The
LRH-1 LBD was identified as mainly hydrophobic and as one of the largest in the NR
family. Three series of analogues have been designed. Steroid-based compounds
bearing a challenging C-2 ether linkage were initially synthesized followed by
analogues structurally related to anti-estrogen agents tamoxifen and
raloxifene (Scheme 0).
[diagram included in print copy, unable to reproduce electronically]
Scheme 0 – Three series of virtual LRH-1 antagonists from our CADD approach [diagram label]
Date Issued
2011-09
Date Awarded
2011-12
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Barrett, Anthony
Sponsor
Cancer Research UK
Creator
Rey, Jullien
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)