Development of MD77, a direct STAT3 inhibitor

Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic latent protein playing a key role, in physiological conditions, for cell survival and proliferation. [1-2] STAT3 is constitutively activated in a wide range of solid and haematological cancers, therefore blocking aberrant STAT3 signaling in tumor cell lines could be a promising therapeutic strategy.[3] During our ongoing researches, [4-6] focused on the development of small molecules targeting STAT3, we identified the oxadiazole derivative MD77,[4,5] a STAT3 SH2 domain direct inhibitor, which showes an interesting antiproliferative activity. On these bases we explored the substitution of the oxadiazole ring with several bioisosteric heterocycles, such as isoxazole and imidazole, to evaluate their effect on the activity (compounds 1-8 general structure). The syntheses and the biological evaluation (STAT3 inhibition and off-target activity) of the novel derivatives will be presented.