果冻传媒

Nuclear receptors (NRs) are transcription factors that control key cellular processes in the body, including metabolism and the immune system. Their activity is regulated by small molecules which makes these proteins an important class of drug targets.

Nuclear receptors as binding sites for drugs
Dysregulation of NRs causes havoc in the body, resulting in diseases ranging from autoimmune disorders to cancer. Studying NRs is complex, as each NR has its own set of ligands and the consequence of ligand binding can differ between NRs. The ability of NRs to bind to different substances makes them interesting targets for the development of new medicines. Although the modulation of endocrine NRs has been highly successful in the clinic, challenges remain in addressing both established and emerging NR targets.

Fascinated with nuclear receptors
As a bachelor student took a class in chemical biology from Luc Brunsveld, who later became his promotor. His enthusiasm for these receptors grew during his master鈥檚 and he decided to do a PhD dedicated to study the workings of NRs.

鈥淎t first, we didn't know exactly what my research would focus on鈥�, says Oerlemans, 鈥渆xcept for 鈥榮omething with nuclear receptors鈥�. This added an additional challenge at the start of my PhD.鈥�

The main goal was to increase fundamental knowledge on two NRs: PPAR纬, a well-known target of diabetes drugs, and NR2F6, a receptor recently identified as a potential target for cancer therapy.

An established receptor with severe side effects
PPARy is a nuclear receptor that plays a crucial role in regulating metabolism and its dysregulation can contribute to type II diabetes. PPARy is a target for drugs to improve insulin sensitivity and lipid metabolism.

However, full activation of PPARy causes severe side effects in patients. Oerlemans experimented with a new class of compounds designed to partially activate the receptor, aiming to reduce side effects while maintaining therapeutic effects.

A promising new receptor to treat cancer
To explore new cancer treatment approaches, Oerlemans set his eye on a relatively unknown receptor: NR2F6. This receptor acts as an immune checkpoint, pulling the brake on the anti-tumor immune response. In cancer cells, it has been shown to drive tumor-promoting properties. This dual activity makes NR2F6 an attractive target in cancer therapy.

However, NR2F6 is poorly understood in terms of its function at the molecular level and no molecules are available to control the activity of this receptor. This is what Oerlemans has set out to improve.

Controlling NR2F6 behaviour
As a molecular mechanic Oerlemans studied the workings and behaviour of NR2F6. When the NR binds to different substances, its shape and function change accordingly.

Oerlemans tested collections of small proteins (peptides) to find partner proteins of NR2F6. 鈥淏y identifying peptides that interact with NR2F6, we developed assays to study NR2F6 activity and determined the first molecular structure of this receptor bound to such a peptide.鈥�

Using this structural information, Oerlemans and his colleagues from the Chemical Biology group gained new insights into NR2F6 function and developed a method to precisely control NR2F6 activity by targeting a specific part of the receptor near the peptide binding site.

Screening for novel NR2F6 modulators
Finally Oerlemans screened a large library of molecules for compounds that control NR2F6 activity. 鈥淲e found several compounds that activate or inhibit NR2F6 activity, offering promising starting points for the development of drugs targeting NR2F6.鈥� 

While NR2F6-targeting medicines are still very much a thing of the future, understanding nuclear receptors and identifying compounds that bind to them is a first crucial step to develop novel treatments.

PhD thesis: . Promotors: Luc Brunsveld and Christian Ottmann.