172286-77-0

Homocarbonyltopsentin (PK4C9) is a small-molecule TSL2-binding compound, binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced SMN2 exon 7 (E7) splicing with EC50 value of 16 μM[1].

PK4C9 is a splice modulator of survival of motor neuron gene SMN2 th at increases production of full-length SMN protein. Spinal muscular atrophy (SMA) is a motor neuron disease caused by deficiency in SMN protein resulting from loss of expression of the SMN1 gene. The related SMN2 gene can compensatebut polymorphism in SMN2 often results in altered splicing and exclusion of exon 7which is required for a full-length SMN transcript. PK4C9 binds to pentaloop conformations of the stem-loop RNA structure TSL2a cis-regulatory element for E7 inclusionand promotes a shift to triloop conformations th at display enhanced E7 splicing. In SMA cellsPK4C9 increased E7 inclusion by 40% accompanied by a 1.5-fold increase in SMN proteina level shown to reverse SMA phenotypes in mice models.

[1] Garcia-Lopez A, et al. Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes. Nat Commun. 2018 May 23;9(1):2032. DOI:10.1038/s41467-018-04110-1