Topical Administration of Novel FKBP12 Ligand MP-004 Improves Retinal Function and Structure in Retinitis Pigmentosa ModelsLara-López, Gonzalez-Imaz, Rodríguez-Hidalgo
et alInvest Ophthalmol Vis Sci (2025) 66 (3), 56
Abstract: This study evaluates the therapeutic potential of MP-004, a novel FKBP12 ligand, in the treatment of inherited retinal dystrophies (IRDs). MP-004 targets the FKBP12/RyR interaction, which is disrupted in several neurologic disorders with underlying oxidative stress.The toxicity and efficacy of MP-004 were examined in vitro in 661W cells. Efficacy was evaluated in phototoxic and H2O2-induced damage using impedance assays, calcium imaging, and in situ PLA. In vivo, MP-004 efficacy was evaluated in the rd10 mouse model of retinitis pigmentosa (RP) by topical ocular instillation. Retinal function was assessed by electroretinography (ERG), visual acuity was measured using a water maze test, and retinal structure was analyzed morphometrically.MP-004 exhibited low toxicity (LD50: 1.22 mM) and effectively protected 661W cells from phototoxicity (EC50: 30.6 nM). Under oxidative stress conditions, MP-004 preserved the FKBP12.6/RyR2 interaction, restored cytosolic and endoplasmic reticulum calcium levels, and prevented cell death. In vivo, MP-004 significantly preserved retinal function in rd10 mice, with ERG wave amplitude increases of up to 50% in scotopic and 71% in photopic conditions, corresponding to rod and cone functions, respectively. Additionally, MP-004 improved visual acuity for low spatial frequency patterns and preserved retinal structure, with a 23% increase in outer nuclear layer thickness and preservation in the number of rods and cones and their segment length.MP-004 shows promise as a therapeutic agent for RP, preserving retinal structure and function, likely through modulation of the FKBP12.6/RyR2 interaction. Further studies are needed to explore its pharmacokinetics and efficacy in other IRD models.
Identification and characterization of ternary complexes consisting of FKBP12, MAPRE1 and macrocyclic molecular gluesSalcius, Tutter, Fouché
et alRSC Chem Biol (2025)
Abstract: Many disease-relevant and functionally well-validated targets are difficult to drug. Their poorly defined 3D structure without deep hydrophobic pockets makes the development of ligands with low molecular weight and high affinity almost impossible. For these targets, incorporation into a ternary complex may be a viable alternative to modulate and in most cases inhibit their function. Therefore, we are interested in methods to identify and characterize molecular glues. In a protein array screen of 50 different macrocyclic FKBP12 ligands against 2500 different randomly selected proteins, a molecular glue compound was found to recruit a dimeric protein called MAPRE1 to FKBP12 in a compound-dependent manner. The corresponding ternary complex was characterized by TR-FRET proximity assay and native MS spectroscopy. Insights into the 3D structure of the ternary complex were obtained by 2D protein NMR spectroscopy and finally by an X-ray structure, which revealed the ternary complex as a 2 : 2 : 2 FKBP12 : molecular glue : MAPRE1 complex exhibiting multiple interactions that occur exclusively in the ternary complex and lead to significant cooperativity α. Using the X-ray structure, rationally guided synthesis of a series of analogues led to the cooperativity driven improvement in the stability of the ternary complex. Furthermore, the ternary complex formation of the series was confirmed by cellular NanoBiT assays, whose A max values correlate with those from the TR-FRET proximity assay. Furthermore, NanoBiT experiments showed the functional impact (inhibition) of these molecular glues on the interaction of MAPRE1 with its intracellular native partners.This journal is © The Royal Society of Chemistry.
Knockdown of FKBP12.6 may Cause Bladder Dysfunction in Mice by Affecting IP3R/TRPM4 FunctionZhao, Zhou, Wang
et alCurr Med Chem (2025)
Abstract: FKBP12.6 is a crucial calcium regulatory molecule involved in the regulation of bladder excitatory contraction. This study employed FKBP12.6 knockout mice to investigate the impact of FKBP12.6 on the expression and function of IP3R/TRPM4 and its subsequent effect on bladder contraction function.The study selected 129S2/SvPasCrl and FKBP12.6 knockout mice and constructed a Partial Bladder Outlet Obstruction (PBOO) mouse model. GSE1595 data were utilized to analyze calcium signaling pathway changes. Void spot assays, urodynamic tests, and visceromotor response were employed to evaluate bladder function, while HE staining was used to assess bladder morphology. Immunofluorescence, co-immunoprecipitation, and Western blot techniques were employed to detect the localization, expression, and binding changes of FKBP12.6, Inositol-1,4,5 trisphosphate Receptor (IP3R), and TRPM4.FKBP12.6 was significantly downregulated in PBOO mice (0.9998±0.07 vs. 0.2911±0.04; p <0.05). The micturition frequency (31.42±4.93 vs. 12.17±3.186), bladder sensitivity (1.59 ± 0.22 vs. 3.57± 0.43; p<0.01), detrusor instability, and muscle strip sensitivity (3.470.51 vs. 5.77±0.35; p<0.01) were increased significantly in FKBP12.6 Knockout (KO) mice (p <0.05). FKBP12.6 knockout did not affect the expressions of IP3R and TRPM4 proteins, but FKBP12.6 directly bound to IP3R in mouse bladder detrusor. IP3R/TRPM4 pathway inhibitors, 2-APB and 9-PHE, notably inhibited detrusor sensitivity, micturition frequency, and urination urgency in FKBP12.6 KO mice.The expression of FKBP12.6 was decreased in the bladder of PBOO mice, and the deletion of FKBP12.6 may lead to bladder dysfunction in mice by affecting the functional activity of IP3R/TRPM4.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1G93A amyotrophic lateral sclerosis (ALS) miceMoreno-Martinez, Gaja-Capdevila, Mosqueira-Martín
et alBr J Pharmacol (2025)
Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons, characterized by dysregulated Ca2+ influx and buffering in early ALS-affected motor neurones. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular Ca2+, as a therapeutic target.A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the superoxide dismutase 1 (SOD1)G93A mouse model of ALS. Different outcomes were used to assess treatment efficacy, including electrophysiology, histopathology, neuromuscular function and survival.Among the novel FKBP12 ligands, MP-010 was chosen for its central nervous system availability and favourable in vitro pharmaco-toxicological profile. Chronic administration of MP-010 to SOD1G93A mice produced preservation of motor nerve conduction, with the 61-mg·kg-1 dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates and significant preservation of motor neurones in the spinal cord of treated mice. Notably, MP-010 treatment significantly extended lifespan by an average of 10 days compared to vehicle.FKBP12 ligands, particularly MP-010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.© 2025 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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