SMN2 modulator-1

SMN2 modulator-1 is a brain-penetrant survival motor neuron (SMN) modulator. SMN2 modulator-1 post-translationally stabilizes SMN protein and increases SMN protein levels independent of SMN2 transcription. SMN2 modulator-1 can be used for the research of spinal muscular atrophy^[1]. In Vitro:SMN2 modulator-1 (Compound 27) (0.29-30 μM; 24 h) potently activates SMN2 expression in SMN2 reporter cells with an EC₅₀ of 0.29 μM, reaching 190% of control activity^[1].
SMN2 modulator-1 (0.4-10 μM; 48 h) increases SMN protein levels in GM003813T SMA patient fibroblasts by approximately 2-fold at a 2 μM 48 h treatment, in a dose-dependent manner^[1].
SMN2 modulator-1 has a kinetic solubility of 31 μM at pH 7.4, a mouse liver microsome half-life of 39 min, human liver microsome half-life of >120 min, and mouse plasma half-life of 326 min^[1].
SMN2 modulator-1 (1-30 μM; 30 min-8 h) does not inhibit the proteasome or autophagy in HEK293 cells, nor does it inhibit HPV-16 E6 mediated p53 degradation in vitro, indicating its SMN-stabilizing effect is not due to global protein degradation inhibition^[1].
SMN2 modulator-1 shows adequate intestinal permeability in the Caco-2 cell model, with an apical-to-basal P_app of 15 × 10^-6 cm/s^[1]. In Vivo:SMN2 modulator-1 (Compound 27) (20 mg/kg; i.p. or p.o.; single dose) achieves high plasma and brain exposure with favorable brain-to-plasma ratios after single intraperitoneal dosing, while oral dosing at the same dose results in moderate, lower exposure in adult mice^[1].