Structural optimization and preclinical validation of ABCB4 correctors – SOPREVAC

Bile secretion facilitates the digestion of dietary fats and the elimination of endogenous and exogenous toxic substances. This vital function is carried out by the liver and begins at the canalicular membrane of hepatocytes, wherein transmembrane proteins such as the ABCB4 transporter secrete phospholipids into bile. Genetic variations of this transporter are associated with several rare cholestatic diseases, the most severe of which is progressive familial intrahepatic cholestasis type 3 (PFIC3). In the absence of effective treatment for severe forms of these diseases, the only option for patients mostly remains liver transplantation. To address this unmet medical need, we have previously identified several families of molecules capable of restoring the intracellular trafficking of ABCB4 variants that are abnormally retained in the hepatocyte cytoplasm. Despite their strong efficacy in correcting this trafficking defect, these molecules also exhibited significant inhibition of the transporter’s phospholipid secretion activity, thereby posing a major challenge to their clinical application.
Building on these findings, we aim to chemically optimize the previously identified molecules to enhance their correction/inhibition ratio and improve their potential as drug candidates. To this end, we will first synthesize new molecules belonging to the previously identified chemical families. Their ability to restore the canalicular targeting of deficient ABCB4 variants will then be assessed in vitro using cell models expressing these variants, thereby mimicking the pathological condition. In parallel, structural analyses, molecular dynamics simulations, and in silico docking studies will be conducted to elucidate how these small molecules interact with ABCB4 and to build their structure-activity relationships (SAR). These iterative approaches that combine chemical synthesis, in vitro studies and computational chemistry, should allow us to identify the most promising compounds as potential drug candidates. Finally, the most effective molecule(s) will be tested in a mouse model that recapitulates the pathological condition, a model currently under development in our laboratories. Our results will then be disseminated through scientific publications, conference presentations, and public outreach efforts, and, if applicable, by filing a patent (prior to any external disclosure).
This research project follows a translational “bedside-to-bench-to-bedside” strategy aimed at identifying small molecules with therapeutic potential as an alternative to liver transplantation for patients with rare and severe cholestatic liver diseases linked to ABCB4 deficiencies. This collaborative and iterative project is poised for success, driven by the combined expertise of the involved partners in chemical synthesis, computational chemistry and in vitro and in vivo approaches. The impact of this research is expected to be multifaceted, advancing scientific and technological knowledge through new experimental tools and novel molecular entities, while also fostering the development of cost-effective pharmacotherapies. These ramifications are expected to generate significant economic and societal benefits while improving patients’ quality of life.