The solute carrier (SLC) family of metabolite transporters gate the movement of hundreds of metabolites across cell membranes. The precise control of metabolite location within cells, tissues, organs, and systemic circulation by SLC transporters is essential for effective metabolism and human health, but has often been overlooked.
Human biology, including human genetics, is increasingly revealing the crucial roles individual SLC transporters play in health and disease. Despite this, fewer than 20 of the 450 SLC transporters are targeted by approved drugs — underscoring a massive untapped therapeutic opportunity.
SLC transporter drug discovery has dramatically lagged behind that for other druggable target classes due to a dearth of effective discovery technologies. Most of the current SLC transporter drugs were initially discovered serendipitously through phenotypic screening, with the transporter identified as the target many years later. Traditional drug discovery approaches, when pursued, have often proven ineffective for SLC transporters. For instance, these integral membrane proteins are largely recalcitrant to biochemical and biophysical approaches and developing drug-like molecules that target the active site is challenging.
Jnana has developed a novel and highly effective cell-based drug discovery platform called Reactive Affinity Probe Interaction Discovery (RAPID) that addresses these obstacles.
RAPID enables targeted screening in live cells for allosteric binders (Reactive Affinity Probes or RAPs) for targets of interest. These RAPs are then leveraged to generate lead-like molecules via medicinal chemistry optimization or high-throughput screening (see image below). Identifying novel allosteric sites, and ligands which bind at these sites, directly in living cells provides a powerful binding-based approach to drug discovery1. By successfully focusing this target-agnostic platform on SLC transporters, we have opened up for the first time the systematic discovery of small-molecule modulators for this target class.
Leveraging the RAPID platform, we are advancing a pipeline of programs in immune-mediated and neurological diseases. Jnana’s targets are grounded in human disease biology, and metabolite levels provide a powerful mechanistic biomarker to guide translation.
Human genetics points to metabolites as critical disease-relevant regulators of immune cell function, opening up novel therapeutic approaches for immune-mediated diseases. We are advancing therapeutics targeting SLC transporters as a differentiated approach to regulating “immunometabolism” pathways to treat inflammatory disorders. The effect of metabolites in the local tissue environment is also critical in inflammation. For Inflammatory Bowel Disease (IBD), which occurs in the metabolite-rich environment of the gut, we are developing therapeutic approaches that address innate immune pathways and gut barrier dysfunction2,3,4.
SLC transporters have already been successfully drugged to treat a number of serious neurological diseases. For instance, Prozac and other selective serotonin reuptake inhibitors (SSRIs) target the serotonin transporter to treat psychiatric disorders. We are pursuing first-in-class therapies for currently untreated monogenic diseases, including Creatine Transporter Deficiency. We also have a research collaboration with Neurocrine Biosciences aimed at discovering novel small molecule therapeutics for multiple targets for central nervous system (CNS) disorders.
1 A Chemical Biology View of Bioactive Small Molecules and a Binder-Based Approach to Connect Biology to Precision Medicines, Stuart L. Schreiber, Isr J Chem, 2019.
2 Therapeutic Opportunities in Inflammatory Bowel Disease: Mechanistic Dissection of Host-Microbiome Relationships. Ramnik J Xavier and colleagues, Cell, 2019.
3 Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Aviv Regev, Ramnik J. Xavier, and colleagues, Cell, 2019.
4 Fine-mapping Inflammatory Bowel Disease Loci to Single-Variant Resolution, Jeffrey C. Barrett, Mark J. Daly, Michel Georges, Ramnik J Xavier and colleagues, Nature, 2017.