Our research addresses ligand-sensing transcription factors (nuclear receptors) as (potential) drug targets. These proteins translate small molecule ligand signals into adaptions in gene expression. We study the medicinal chemistry of nuclear receptor ligands and develop nuclear receptor modulators as tool compounds with a particular focus on nuclear receptors involved in neuro-protection and neurodegeneration.

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 RXRagonists. 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 RXRligands 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, the second member of the nerve growth factor-induced b subfamily of orphan nuclear receptors, is a neuroprotective transcription factor mainly found in the central nervous system with high expression in neurons. Several lines of evidence point to a remarkable potential of Nurr1 in neurodegenerative diseases. Altered Nurr1 expression levels have been detected in Parkinson’s Disease, Alzheimer’s Disease and Multiple Sclerosis patients, and Nurr1 expression was also diminished in rodent models of these diseases. In experimental autoimmune encephalomyelitis which is a common rodent model of multiple sclerosis, heterozygous Nurr1 knockout mice developed the disease faster than wild-type mice. Moreover, neuronal Nurr1 knockout in mice caused a phenotype resembling early Parkinson’s Disease. Hence, Nurr1 presents as a very 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. A clear endogenous Nurr1 ligand is also lacking but recent research has demonstrated that Nurr1 can accommodate ligands and that Nurr1 activity can by controlled by small molecules. Still, no potent and selective Nurr1 modulators are available as tool compounds for pharmacology. To overcome this critical 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 and role in disease.

Tailless homologue (TLX)

TLX (human tailless homologue of Drosophila, NR2E1) is considered as a master regulator of neurogenesis and essential for CNS development. In adults, TLX 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 proliferating state. In vivo studies have demonstrated that disruption of TLX expression causes behavioural deficits (aggressiveness, impaired cognitive functions, bipolar disorder, schizophrenia) and malformation of brain structures. Therefore, TLX appears as a very promising target to counteract neurodegenerative disorders. TLX ligand discovery, however, is at a very early stage as only few small molecules are known to bind or modulate TLX. To close this gap, we search for new TLX ligand chemotypes 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.