A new series of hydrazine-bearing Class I selective HDAC inhibitors was designed and synthesized based on the modification in three parts (cap, linker and ZBG) of panobinostate. The representative compound LP97 exhibited potent activity against class I HDAC1, 2 and 3, with the IC50 value of 5.17 nM, 49.5 nM, and 0.53 nM, respectively, while with no activity towards HDAC6 up to 50,000 nM. EC50 of LP97 against wt-p53 MV4-11 cell was 15.35 nM. Differential toxicity profile for LP97 toward multiple malignant tumor cells with diverse p53 status. The western blot study revealed the mechanism of LP97's cytoxicity involved in regulations of FLT3/STAT5 (oncogenic signaling), p53 (tumor repressor/oncogene), and HDAC6/tubulin (heat-shock and proteasomal/lysosomal regulation and trafficking). Furthermore, we demonstrated instead of apoptosis, cellular autophagy is the key factor triggered cell death as cell death can be attenuated by autophagy inhibitor chloroquine other than pan-caspase inhibitor z-VAD. Althougth compound LP97 showed a little lower potency than panobinostate, it displayed HDAC class I selective profile and could't increase Hsp70 up-regulation. When compared with the parent panobinostate, LP97 were not mutagenic and showed better bioavailability and half-lives with a higher Cmax and a longer t1/2, which suggest that LP97 is likely to have significantly better bioavailability and half-lives than panobinostate.

Discovery of hydrazine-bearing selective HDAC inhibitor based on panobinostate: Structure-activity relationship, anti-tumor mechanism and pharmacokinetics study

255th National Meeting (2018)

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