Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) Inhibitors for Treating Obesity-Induced Pathologies [Technology offer]

Small molecule inhibitors of Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) for use in the treatment of obesity and obesity-induced pathologies including metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC).

Obesity, which affects more than 650 million individuals worldwide, is a well-established risk factor for MASLD which can in turn progress to HCC. With an increasing number of patients developing obesity-related liver complications, there is a pressing need to develop drugs based on new therapeutic approaches for the treatment of such diseases. Protein Tyrosine Phosphatases represent in this perspective a new class of emerging drug targets of specific interest, remaining still largely unexplored.       

Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent MASLD. Obesity leads to dysregulated expression of hepatic protein tyrosine phosphatases (PTPs). Among PTPs, PTPRK has been found by the inventors to be increased in steatotic hepatocytes and positively correlated with lipogenic signaling. In addition, the inventors demonstrated that silencing PTPRK in hepatoma cell lines resulted in reduced colony-forming ability and that PTPRK knock-out mice developed smaller tumours upon hepatocarcinogenesis induction, thereby shedding light on the key role of PTPRK in regulating hepatic glycolysis, lipid metabolism and tumour development.

In this context, the inventors have developed a series of small molecules PTPRK inhibitors providing new therapeutic possibilities for the treatment of obesity-associated liver diseases. The hit compounds series present a high stability and molecular affinity for the catalytic site of PTPRK and are amenable to a drug development program further to the validation of their specific inhibition activity on the PTPRK target through enzymatic activity assays using the recombinant PTPRK intracellular domain. The first in vitro results on cell lines also confirm the effect of those small molecules inhibitors on cancer cell lines growth. Pre-clinical in vivo studies in C57BL/6 mice demonstrate in addition that those compounds also induce a decrease of weight and body fat in obese mice opening thereby opportunities for obesity treatment.

1. Inhibition of PTPRK’s catalytic activity with IC₅₀ in the µM range amenable to lower concentrations upon hit to lead optimization.
2. In vitro inhibition of cancer lines growth.
3. In vivo demonstration of body fat reduction upon treatment of obese mice.
4. Small molecules presenting no toxicity as assayed on Zebrafish larvae.

• Treatment of obesity
• Treatment of obesity induced HCC and other related hepatic diseases, such as MASLD

H) In vivo assessment of PTPRK Inhibitor 2 was conducted in C57Bl/6 male mice. The mice were treated with vehicle or 50mg/kg PTPRK Inhibitor 2 for 5 days.
(I-L) Body weight was measured daily (I), and body composition were measured before and after the treatment (J).
Liver composition analysis was performed (K) and glycaemia levels were assessed daily (L).
The reported data are presented as mean±SEM. Statistical significance is indicated as * p<0.05, ** p<0.01, *** p<0.001.

*What's TRL?

TRL-3 Proof of concept: in vitro inhibition of hepatic cancer lines and first in vivo results showing potential for development of obesity treatment.

Prof Esteban Gurzov has dedicated his scientific career to investigate the pathogenic mechanisms of obesity and diabetes and the discovery of novel therapeutics. In 2017, he received a tenured Associate Researcher/Chercheur Qualifié position from the FRS-FNRS to direct the Signal Transduction & Metabolism Laboratory. In 2019, he was awarded with a European Research Council (ERC) Consolidator Grant and was recipient of one of the 2021 AstraZeneca Foundation Award. Since 2019, he is also affiliated as WELBIO Investigator of the Walloon Excellence Research Institute (WELRI).

The Signal Transduction & Metabolism Laboratory, located on the academic hospital campus aims at translating research discoveries to the clinic through a combined use of molecular biology, stem cells research, animal models of metabolic disorders and human samples.

Prof José Antonio is a specialist in structural proteomics and bioinformatics and has in this framework been very active in the in silico design of peptidic protein-kinase inhibitors. His expertise also encompasses molecular docking approaches for drug discovery including research on inhibitors of Dengue and Zika RNA-dependent RNA polymerase and more recently on Protein Tyrosine Phosphatases inhibitors. He heads the Bioactive Molecules Design and Development research group at the Institute of Research, Development, and Innovation in Healthcare Biotechnology of the Miguel Hernandez University at Elche that he joined in 1997 after several post-doctoral stays including at University of Amsterdam, and University Paris VII. He also spent 2 years (2004-2006) at the European Molecular Biology Laboratory (EMBL) in Heidelberg where he contributed to the development of the website for ADAN database of protein modular domains implied in protein-protein interactions

• PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity. Nat Commun 15, 9522 (2024) 

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