Nuclear receptors

Nuclear receptors are a family of proteins that act as ligand-activated transcription factors and regulate gene expression depending on ligand binding. 48 nuclear receptors are known in human of which many have pharmacological relevance. Still, several nuclear receptors remain “orphans” meaning that their ligands are unknown and their physiological and pathological roles remain elusive. To capture their pharmacological potential and validate them as targets, potent tool compounds are required.

Retinoid X receptors (RXR)

Nuclear receptors often act as dimers which can be composed of two monomers of one nuclear receptor (homodimer) or involve two different nuclear receptors (heterodimer). The retinoid X receptors (RXRs) are universal partner receptors and form heterodimers with many other nuclear receptors. Many RXR heterodimers respond to ligands of both partners (permissive heterodimers) and, thus, can be activated by RXR agonists. The RXRs are, therefore, involved in numerous physiological and pathological processes. Amongst other promising activities, RXR modulation is ascribed great potential for novel therapeutic strategies in Alzheimer’s disease (AD) and multiple sclerosis (MS). Recent observations, for example, indicate that RXRγ activation can promote CNS re-myelination which would open an avenue to regenerative MS treatment. However, available RXR ligands suffer from poor physicochemical properties and insufficient subtype selectivity. There is an urgent need for innovative RXR ligands with improved physicochemical properties and subtype selective activity. To enable target validation of the individual RXRs in neurodegenerative diseases and beyond, we aim to develop subtype selective RXR activators as pharmacological tools.

Nuclear receptor related-1 (Nurr1)

Nurr1, as a member of the nerve growth factor-induced b subfamily of orphan receptors, is a neuroprotective transcription factor mainly found in the central nervous system with high expression in neurons. Dopamine neuron development in midbrain is Nurr1 dependent and Nurr1 knock-out in mature dopamine neurons in mice resulted in a phenotype resembling early PD. In Parkinson’s Disease (PD) patients, diminished levels of Nurr1 were found. Recently, Nurr1 was also ascribed a crucial role in the pathogenesis of Alzheimer’s disease and multiple sclerosis. Nurr1 thus appears as promising protein target for the treatment of neurodegenerative diseases. Originally, the nuclear receptor was considered as ligand-independent due to its closed ligand-free conformation and its high constitutive activity. To date, also no endogenous ligand has been clearly identified but latest research has demonstrated that Nurr1 can accommodate ligands and that Nurr1 activity can by controlled by small molecules. However, no potent and selective Nurr1 modulators are available that are suitable as tool compounds for pharmacology. To overcome this gap in research on Nurr1, we are developing new modulators for this orphan nuclear receptor as pharmacological tools and study the receptor’s molecular function.

Tailless homologue (TLX)

TLX (human tailless homologue of Drosophila, NR2E1) is considered as a master regulator of neurogenesis. TLX is essential for CNS development and in adults, the receptor is almost exclusively expressed in neural stem cells (NSCs) residing in few areas of the brain. TLX is required to maintain NSCs in an undifferentiated proliferative state. In vivo studies have demonstrated that disruption of TLX expression goes along with behavioural deficits (aggressiveness, impaired cognitive functions, bipolar disorder, schizophrenia) and malformation of brain structures. Therefore, TLX appears as promising target to counteract neurodegenerative disorders. TLX ligand discovery TLX, however, is at a very early stage as only few small molecules are known to bind or modulate TLX. We aim to discover ligands for this orphan nuclear receptor and optimize them towards potent and selective TLX modulators that are useful as pharmacological tools and enable target validation of TLX.

Farnesoid X receptor (FXR)

The farnesoid X receptor (FXR) is a bile acid activated transcription factor with high expression levels in liver, intestine and kidney. It acts as important liver protector and has been identified as therapeutic target for hepatic and metabolic diseases. We aim to develop FXR ligands with a designed polypharmacology profile meaning that they simultaneously modulate a second mode-of-action target. Therein, we select pharmacodynamic activities that hold promise to generate synergies with FXR modulation in non-alcoholic steatohepatitis (NASH) such as inhibition of soluble epoxide hydrolase (sEH) and activation of peroxisome proliferator-activated receptor δ (PPARδ).

Peroxisome proliferator-activated receptors (PPARs)

Peroxisome proliferator-activated receptors (PPARs) are key regulators of lipid and glucose metabolism. PPARα is a major regulator of β-oxidation and lipid transport in liver and other tissues with high lipid metabolic activity. PPARγ is highly expressed in adipose tissue where it governs adipocyte differentiation, adipose tissue homeostasis, lipid metabolism and insulin sensitivity. Ubiquitously expressed PPARδ controls fatty acid utilization for energy generation in skeletal muscle. In addition, PPARs are also found in immune cells and involved in inflammatory processes. While PPARα and PPARγ have relevance as drug targets and many PPAR agonist chemotypes have been developed, knowledge on endogenous PPAR modulators is still limited. In this field, we focus on the discovery of naturally occurring PPAR ligands and on the development of allosteric PPAR binders with selective modulatory properties.

Funding

Our research currently is financially supported by the German Research Foundation (DFG), the Else-Kroener-Fresenius Foundation, the Aventis Foundation, and the German Federal Ministry of Economic Affairs and Energy (BMWi).