Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity

In our previous research, a series of phenylsulfonylfuroxan-basedhydroxamates were developed, among which compound 1 exhibitedremarkable in vitro and in vivo antitumor potency due to its histonedeacetylase (HDAC) inhibitory and nitric oxide (NO)-donating activities.Herein, the in-depth study of compound 1 revealed thatthis HDAC inhibitor-NO donor hybrid could enduringly increase theintracellular levels of acetyl histones and acetyl & alpha;-tubulin,which could be ascribed to its irreversible inhibition toward classI HDACs and HDAC6. Structural modification of compound 1 led to a novel phenylsulfonylfuroxan-based hydroxamate 4, which exhibited considerable HDAC6 inhibitory activity and selectivity.Furthermore, compound 4 could inhibit intracellular HDAC6both selectively and irreversibly. To the best of our knowledge, thisis the first research reporting the irreversible inhibition of HDAC6.It was also demonstrated that compared with ACY-241 (a reversibleHDAC6 inhibitor in clinical trials), the irreversible HDAC6 selectiveinhibitor 4 exhibited not only superior anti-multiplemyeloma activity but also improved therapeutic index.

Automated summary

In our previous research, a compound named 1 showed significant anti-tumor activity due to its HDAC inhibitory and NO-donating properties. Further study revealed that compound 1 could increase acetyl histones and acetyl & alpha;-tubulin levels by irreversibly inhibiting class I HDACs and HDAC6. Modification of compound 1 led to the development of compound 4, which selectively and irreversibly inhibited intracellular HDAC6 and exhibited improved therapeutic index compared to ACY-241.