Download Nuclear Receptor Program Fact Sheet Plexxikon

September 2006
2005
Nuclear Receptor Program Fact Sheet
The nuclear receptors are a family of transcription factors which regulate a wide array of biological
processes, including those involved in diabetes, obesity, cardiovascular disease and cancer. Many
important therapeutics, including 12 of the top 100 selling drugs, target nuclear receptors.
Plexxikon has focused discovery efforts on novel therapeutics targeting several members of the
nuclear receptor family, particularly those where known small molecule modulators are limited or
where the limitations of existing therapeutics provide a significant clinical opportunity. Among the
company’s discovery programs, a pan compound targeting PPAR α, δ and γ for Type II diabetes and
related cardiovascular disorders is most advanced at the clinical development stage.
Plexxikon pursues drug discovery in nuclear receptors through a strategy to access low molecular
weight chemical scaffolds that have previously not been exploited. Plexxikon’s Scaffold-Based Drug
DiscoveryTM starts with screening of the company’s compound library to identify low molecular
weight, low affinity compounds with activity against multiple members or isoforms of the nuclear
receptor family. Structural analysis based on co-crystallography of the active compounds leads to the
selection of certain compounds as scaffold candidates – those compounds which exhibit a dominant
binding mode and have appropriate sites for substitution, tractable chemistry and novel intellectual
property potential. In a subsequent step, Plexxikon validates candidate scaffolds by synthesizing and
evaluating a small exploratory library. Such validated scaffolds can then be employed as starting
points for individual discovery programs targeting specific nuclear receptors.
Plexxikon Scaffold-Based Drug DiscoveryTM Process
Validated scaffolds
Lead discovery &
Optimization for
specific target
Compound library
screening hits
(low affinity)
Co-crystallography
Chemical tractability
Side-chain enumeration
Parallel synthesis
Exploratory library
Biochemical assay
Co-crystallography
Plexxikon has applied this strategy to identify multiple novel scaffolds for PPARs. A series of novel
pan-active compounds that target all three PPAR subtypes (α, γ, and δ) has been developed. In vivo
PK and efficacy studies testing these lead compounds have demonstrated excellent PK properties
and biological activities and represent a novel class of potential therapeutics for Type II diabetes and
associated syndromes. Other nuclear receptor discovery efforts are focused on orphan receptors
involved in cholesterol and bile acid metabolism (LXR, FXR, HNF4, LRH-1, SHP) and steroid
synthesis (SF-1, DAX), classic endocrine receptors (VDR, TR), and steroid receptors (GR, AR).
Nuclear Receptor Program Fact Sheet
Selected Plexxikon Nuclear Receptor Co-Crystals
Among the key strengths of Plexxikon’s platform is the capability to screen low molecular weight
“scaffold-like” compounds, and to apply structural screening at an early point in lead finding. This
approach addresses a key challenge in drug discovery today: how to discover novel lead
compounds targeting members of a particular protein family rapidly and efficiently. By using X-ray
crystallography to aid in the mining of largely unexplored chemical space, Plexxikon develops a
structure-guided road map for the efficient discovery and optimization of unique compounds with
remarkable bioactivity.
Plexxikon is seeking to collaborate
Novel LXR Scaffold
GR Structure
with pharmaceutical partners with
strong clinical development expertise
in
diseases
involving
nuclear
receptors. A collaboration may be
based on a single drug target or
multiple targets in a common
biological pathway. In such a
collaboration Plexxikon would provide
novel, potent and selective lead
1.5 Å
compounds as clinical candidates for
further development by the partner.
Phospholipids Identified As Ligands For
Human SF-1 and LRH-1
L378
SF-1
L344
Y470
Y436
T377
K474
K440
G341
Wang et al. PNAS 102, 7505-10, 2005.
LRH-1
Contact:
Kathleen Sereda Glaub
Plexxikon Inc.
President
Phone: 510.647.4009
Fax: 510.548.8014
[email protected]
www.plexxikon.com