Innovative allosteric inhibitors are coming to the clinic

Jnana Therapeutics announced that it has selected JNT-517 as a development candidate and potential "first-in-class" oral approach for the treatment of phenylketonuria (PKU). This is a rare genetic metabolic disease. The company plans to launch a Phase 1 clinical trial evaluating JNT-517 later this year.

PKU is caused by phenylalanine hydroxylase (PAH) deficiency. Phenylalanine (Phe) is an amino acid found in all protein-containing foods, and PAH is an enzyme necessary to break down Phe. When PAHs are deficient or functionally deficient, Phe will accumulate to abnormally high toxic levels in the blood. If left untreated, Phe in the blood can lead to progressive and severe neurological impairment and neuropsychological complications. SLC6A19 is a transporter protein responsible for the kidney's reabsorption of Phe back into the bloodstream. Therefore, inhibition of SLC6A19 provides a new approach for the treatment of PKU.

The structure and intracellular location of SLC transporters are highly diverse, often difficult to express and purify, not easy to analyze using biophysical methods, and may not have known ligands. Jnana's chemical proteome platform RAPID, which discovers candidate compounds based solely on the ability of small molecule binding proteins, offers a promising approach for addressing challenging SLC targets. The company recently generated the first cryo-em structure of SLC6A19 with a small molecule ligand complex, revealing a cryptic allosteric site on the SLC transporter where Jnana's proprietary small molecule inhibitors bind.

Upon completion of the study in support of IND authorization, Jnana will initiate a Phase 1 clinical trial to evaluate the safety, pharmacokinetic and pharmacodynamic biomarkers of JNT-517. The trial design will involve single and multiple dose increments in healthy volunteers, followed by inclusion in a cohort of PKU patients to obtain key proof-of-concept data to support subsequent enrollment programs.