ALLO-1 is a small molecule antagonist that inhibits drug-resistant mutant of Smoothened (Smo), related to cancers.
allo-1 is a smo antagonist.hedgehog (hh) proteins are important development regulators that bind the cell-surface protein, which allows the activation of a gpcr-like receptor, smoothened (smo). in vertebrates, the smo activation finally results in the activation of the zinc-finger transcription factors of the gli family. in addition, the overactivation of smo may lead to certain cancers.
ALLO-1 is a Smoothened (Smo) antagonist that inhibits both wild-type and mutant Smo, including D473H SMO mutant. ALLO-1 binds to a different domain of Smo than other known Smo ligands.
previous study found that allo-1 and its close analog allo-2 could inhibit smo agonist hh-ag 1.5-induced luciferase expression in tm3-gli-luc cells. the potency of allo-1 did not change when either low dose or high dose of hh-ag 1.5 was used, in contrast to other known smo antagonists that are strong sag or hh-ag 1.5 competitors. moreover, it was found that in contrast to gdc-0449, both allo-1 and allo-2 inhibited wild-type and the d477g mutant with only around2-fold shift in ic50, indicating that the d477g mutation did not significantly interfere with the binding of allo-1 and allo-2 to smo. in addition, allo-1 as well as allo-2 were able to inhibit both wild-type and d473h mutant human smo with similar potencies [1].
[1] tao, h. ,jin, q.,koo, d.i., et al. small molecule antagonists in distinct binding modes inhibit drug-resistant mutant of smoothened. chemistry & biology 18, 432-437 (2011).
