Constitutive activation of STAT3 has been found in a wide variety of cancers, and it has been validated as an attractive therapeutic target. STAT3 SH2 domain inhibitors could compete with the native phosphotyrosine (pTyr) peptide to block both STAT3 activation and dimerization.We have built enrichment libraries from existing STAT3 inhibitors according to their binding poses using fragment-based drug design (FBDD) strategy. Fragments selected from the library were recombined and linked together computationally. Four of the five selected and synthesized compounds have IC50 lower than 5�M for cell line U2OS; among which, LY5 has IC50 range in 0.5~1.4�M in various cancer cell lines. The fluorescence polarization (FP) assay also confirmed that LY5 strongly binds to STAT3 SH2 domain biochemically. The study has proved the feasibility of in silico site-directed FBDD for STAT3 drug discovery.

Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design

244th National Meeting (2012)

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