A Novel, Long-Acting, Small Molecule PKM2 Activator and Its Potential Broad Application Against Photoreceptor Degeneration.

Purpose: Activating pyruvate kinase M2 (PKM2) has been shown to be neuroprotective in preclinical models of photoreceptor degeneration. We recently developed novel, small molecule activators for ocular delivery. Here, we sought to characterize the ocular pharmacology, toxicity, and efficacy of MCTI-566, a novel PKM2 activator, to translate this therapeutic strategy to the clinic. Methods: X-ray protein crystallography and isothermal titration calorimetry assessed the interaction of MCTI-566 with PKM2. PKM2 activation and tissue pharmacokinetics were examined after intravitreal or systemic administration of MCTI-566. Retinal toxicity was evaluated in rats after intravitreal injection. The effect of MCTI-566 on photoreceptor death was assessed using in vitro and in vivo models of outer retinal stress and on the inflammatory response in the rd10 retina using flow cytometry and quantitative real-time polymerase chain reaction. Results: The PKM2-MCTI-566 co-crystal structure demonstrated a binding pocket distinct from endogenous activators. MCTI-566 increases retinal PK activity 200% following intravitreal or systemic administration. MCTI-566 distributed to the retina after intravitreal or systemic administration, activated the target for ≥90 days and was specific for photoreceptor PKM2. No retinal toxicity was observed after repeated intravitreal administration. MCTI-566 reduced photoreceptor apoptosis in a model of retinal detachment, and delayed photoreceptor degeneration and altered the inflammatory response in the rd10 retina. Conclusions: MCTI-566 is a small molecule drug candidate for photoreceptor neuroprotection. Translational Relevance: MCTI-566, a long-acting and well-tolerated ocular PKM2 activator, may be a potential therapeutic to combat currently untreatable retinal degenerations.