KYN-5356

Mechanism of action

Potent, selective, reversible, brain-penetrant small-molecule inhibitor of kynurenine aminotransferase II (KAT-II; gene AADAT, also KAT2/KYAT2; UniProt Q8N5Z0), the mitochondrial aminotransferase that performs the bulk of the irreversible transamination of L-kynurenine to kynurenic acid (KYNA) in the human brain. KYNA is an endogenous inhibitor of the alpha-7 nicotinic acetylcholine receptor and of the NMDA receptor, both required for normal cognition, and KYNA is consistently elevated in the brain and CSF of people with schizophrenia; preclinical work shows KYNA modulates cognition bidirectionally, with raised KYNA impairing and lowered KYNA improving performance. Inhibiting KAT-II therefore lowers KYNA and is expected to disinhibit both cholinergic and glutamatergic transmission. In cynomolgus monkeys and marmosets, KYN-5356 showed adequate bioavailability and brain penetration and dose-dependently reduced the KYNA/L-kynurenine ratio in hippocampus and prefrontal cortex by up to about 50% at the highest dose tested; intrahippocampal infusion produced a robust, steady rise in extracellular acetylcholine; and systemic dosing increased cognitively relevant alpha and beta EEG band activity and attenuated scopolamine-induced delta (>50% reduction) and theta (near-complete block) increases, indicating enhanced cholinergic transmission beyond simple alpha-7 disinhibition. In the first-in-human study, CSF KYNA fell dose-dependently and EEG measures linked to cognitive pathways changed significantly, confirming central target engagement. No absolute potency figure (IC50/Ki) or selectivity fold has ever been published for KYN-5356.

Formulations

KYN-5356 for Schizophrenia

Phase 2RecruitingSchizophrenia indication →

KYN-5356, a first-in-class KAT-II inhibitor, as adjunctive treatment for cognitive impairment associated with schizophrenia (CIAS) — Kynexis's lead and only disclosed clinical program. CIAS remains a completely unmet need: no drug is approved for it, and the field is littered with negative trials. The pivotal-path-defining study is KYN5356-CL-002 (NCT07191483), a randomized, double-blind, placebo-controlled Phase 2 proof-of-concept trial in 150 clinically stable adults with schizophrenia aged 18-55, testing three blinded dose levels of KYN-5356 against placebo over 28 days of adjunctive treatment; the primary endpoint is change from baseline at Day 28 in the digital Brief Assessment of Cognition in Schizophrenia (BAC App) composite T-score, with Cmax/AUCtau/Tmax/Ctrough/t1/2 as secondary endpoints and an EEG substudy of roughly 75 participants. The design deliberately engineers against the historical failure modes of CIAS trials: a small number of highly experienced sites, an inpatient setting with laboratory-confirmed antipsychotic adherence, a computerized BACS administered three times before randomization to wash out practice effects, enrichment by a minimum baseline cognitive-deficit threshold, exclusion of participants whose pre-randomization BACS moves substantially, and close sponsor oversight of rater quality. The 28-day duration is justified by the rapid, mechanism-linked BACS and pharmacodynamic changes seen in the first-in-human study. The study started 27 August 2025 (registry actual), first patient dosed was announced 30 September 2025, it is recruiting at 15 US sites as of the registry's 23 June 2026 update, and topline is guided to Q4 2026. Preceded by the completed 72-subject Phase 1 (NCT06225115), which was positive on safety and showed dose-dependent CSF KYNA reduction plus significant EEG changes. No regulatory designation, no partnership on the asset itself, and no dose-arm drop or safety hold is publicly disclosed.

Clinical trials