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HDAC3 Activity. We first determined the selectivity profile of RGFP-966 against class I HDACs (HDACs 1, 2, 3, and 8) using a cell-free HDAC3 activity assay (Materials and Methods). We observed that RGFP-966 is 3.1±0.05 times more selective for HDAC3 over HDAC1 (P= 0.02) and 5.0±0.2 times more selective for HDAC3 over HDAC2 (P= 0.005). No inhibition of HDAC8 was observed in response to RGFP-966 (SI Appendix, Fig. S1 A). RGFP-966 inhibits HDAC3 with an IC50 of 1.5 μM, HDAC2 with an IC50 of 6.8 μM, and HDAC1 with an IC50 of 4.423 μM (SI Appendix, Fig. S1 A). Suberoylanilide hydroxamic acid (SAHA) was used as a positive control. Next, we used the HEK/APPsw cell line, a well-established AD cellular model, harboring an APP double mutation (KM670/671NL) immediately adjacent to the β-secretase cleavage site (SI Appendix, Materials and Methods) to validate HDAC3 activity following 48 h …