Pascal Heitel

The liver X receptor is a promising target for diseases with dysregulated cholesterol levels. In addition to enhanced reverse cholesterol transport, however, LXR activation induces hepatic lipogenesis. Since the subtype LXRα is dominant in the liver, one strategy to overcome this is the development of LXRβ‐selective agonists. We optimized the reported compound 2 with efficacy‐based preference for LXRβ by scaffold hopping to enhance potency and selectivity. Among the four different scaffolds, which were obtained from computer‐assisted design and subsequent synthesis, compound 7 emerged as the most promising scaffold. The spiro[indan‐1,4′‐piperidine] scaffold of 7 demonstrated superior pharmacokinetic and pharmacodynamic properties, warranting its further investigation towards a pharmacological tool compound.

The Frontiers in Medicinal Chemistry (FiMC) was held in Münster from March 24 ^th to 27 ^th as the largest international Medicinal Chemistry conference in Germany. Welcoming more than 240 participants from around 20 countries, it was a vibrant conference, celebrating the community and the Medicinal Chemistry division of the German Chemical Society (GDCh). The program filled 4 days with over 40 lectures from industry and academia, and 125 posters. Herein, the NextGenMedChem group reports their highlights from this conference.

Silymarin is a mixture of bioactive natural products from milk thistle ( Silybum marianum ) fruit extracts, which have a long history as a phytotherapeutic agent in treating various liver‐related ailments. Even though important pharmacological effects of silymarin, such as the antioxidative properties, have been proven, the exact molecular mechanisms for its liver‐protective action remain elusive. Here, we provide in vitro pharmacological data showing that silymarin, as a mixture and also its individual flavanonol lignans, antagonize liver X receptor (LXR). In HepG2 cells, the isolated silymarin flavanonol lignans showed LXR‐mediated anti‐steatotic effects that may play a crucial role in the hepatoprotective action of silymarin. Our findings underscore the potential of silymarin, both as a mixture and in the form of its isolated flavanonol lignans, as therapeutic agents for liver disorders, including metabolic dysfunction‐associated steatotic liver disease (MASLD). There is an urgent need for well‐designed clinical trials engaging standardized milk thistle fruit extract to explore its efficacy in MASLD.

In 2024, the FDA granted approval for resmetirom, a selective but moderately potent agonist of the thyroid hormone receptor (THR) β, marking the first drug for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) in the US. Given the absence of selectivity data, we conducted a comprehensive screening against other nuclear receptors implicated in metabolic regulation, in addition to THRβ. Reporter gene assays revealed that resmetirom also binds several off-target nuclear receptors, including constitutive androstane receptor (CAR), retinoic acid receptor-related orphan receptors (RORs), and hepatocyte nuclear factor 4α (HNF4α). However, subsequent in vitro experiments, designed to better recapitulate physiological conditions, showed that THRβ modulation is functionally dominant. These preliminary findings suggest that pharmacotherapeutic efficacy of resmetirom remains intact despite the identified off-target effects, supporting its clinical application in the treatment of MASH.

Liver X receptors (LXRs) are promising targets for metabolic disorders including atherosclerosis and metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we employed a chemical language model (CLM) for LXR modulator design in an explorative fashion and observed that structural features from different LXR modulator templates were merged, and structure–activity relationship (SAR) knowledge was transferred. The generated computational designs demonstrated LXR modulation with diverse activity profiles and selective modulator properties, including a promising lipolytic activity of an inverse LXR agonist in an in vitro MASLD model that warrants its further development to improve ADME properties.

The nuclear receptors hepatocyte nuclear factor 4α (HNF4α) and retinoic acid receptor‐related orphan receptor‐β (RORβ) are ligand‐regulated transcription factors and potential drug targets for metabolic disorders. However, there is a lack of small molecular, selective ligands to explore the therapeutic potential in further detail. Here, we report the discovery of greater celandine (Chelidonium majus) isoquinoline alkaloids as nuclear receptor modulators: Berberine is a selective RORβ inverse agonist and modulated target genes involved in the circadian clock, photoreceptor cell development, and neuronal function. The structurally related chelidonine was identified as a ligand for the constitutively active HNF4α receptor, with nanomolar potency in a cellular reporter gene assay. In human liver cancer cells naturally expressing high levels of HNF4α, chelidonine acted as an inverse agonist and downregulated genes associated with gluconeogenesis and drug metabolism. Both berberine and chelidonine are promising tool compounds to further investigate their target nuclear receptors and for drug discovery.

Posttranslational modifications (PTMs) play an important role in cell signaling and they are often deregulated in disease. This review addresses recent advances in the development of heterobifunctional small molecules that enable targeting or hijacking PTMs. This emerging field is spearheaded by proteolysis-targeting chimeras (PROTACs), that induce ubiquitination of their targets and, thus, tag them for degradation by the proteasome. Within the last decade, several improvements have been made to enhance spatiotemporal control of PROTAC-induced degradation as well as cell permeability. Inspired by the success story of PROTACs, additional concepts based on chimeric small molecules have emerged such as phosphatase-recruiting chimeras (PhoRCs). Herein, an overview of strategies causing (de-)phosphorylation, deubiquitination as well as acetylation is provided, and the opportunities and challenges of heterobifunctional molecules for drug discovery are highlighted. Although significant progress has been achieved, a plethora of PTMs have not yet been covered and PTM-inducing chimeras will be helpful tools for chemical biology and could even find application in pharmacotherapy.

Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.

Nonalcoholic steatohepatitis (NASH) is considered as severe hepatic manifestation of the metabolic syndrome and has alarming global prevalence. The ligand-activated transcription factors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) δ have been validated as molecular targets to counter NASH. To achieve robust therapeutic efficacy in this multifactorial pathology, combined peripheral PPARδ-mediated activity and hepatic effects of FXR activation appear as a promising multitarget approach. We have designed a minimal dual FXR/PPARδ activator scaffold by rational fusion of pharmacophores derived from selective agonists. Our dual agonist lead compound exhibited weak agonism on FXR and PPARδ and was structurally refined to a potent and balanced FXR/PPARδ activator in a computer-aided fashion. The resulting dual FXR/PPARδ modulator comprises high selectivity over related nuclear receptors and activates the two target transcription factors in native cellular settings.