Novel HDAC Inhibitors as Anti-Cancer Agents


Project: D2014-49



Cancer remains the second most common cause of death, accounting for nearly 1 out of every 4 deaths in the United States. American Chemical Society has estimated diagnosis of more than 1.6 million new cancer cases and deaths of more than 500,000 cancer patients in the US in the year 2014 alone. A promising new anticancer drug development strategy that is being extensively investigated currently is the targeting of epigenetic regulation of gene expression that may be associated with cancer initiation and progression. As histone deacetylases (HDAC) play an important role in gene expression, HDAC inhibitors have become an increasingly popular class of agents for targeting epigenetic regulation. There are currently four HDAC inhibitors approved by the FDA for clinical use; suberoylanilide hydroxamic acid (SAHA) (Vorinostat® or Zolinza®), FK228 (romidepsin®), belinostat (beleodaq®), and panobinostat. However, there is a need for isoform-selective or class-selective inhibitors for higher therapeutic potential and reduced side effects.


Invention description:

In continuation of their endeavors to design and synthesize potent anticancer agents, researchers at the University of Toledo have developed small drug like molecules that have demonstrated high anti-proliferative activity towards various cancer cells. These compounds developed at the university are novel largazole (1) analogues JA1 to JA6, AA1-AA2, and RF1 with major modifications in the depsipeptide ring, while maintaining its 16-membered ring character. It is worth noting that the natural product Largazole is a potent and class I selective HDAC inhibitor isolated from a marine cyanobacterium of the genus Symploca. It is a prodrug that undergoes hydrolysis of the thioester group by cellular esterases and/or lipases to release a free thiol function which constitutes the domain that chelates Zn2+.

These analogues were tested in the National Cancer Institute (NCI) sixty human tumor cell line assay (NCI-60), where the antiproliferative activities of the compounds were screened initially at a single dose of 10 µM, followed by dose response assay. These analogues showed significant activity on several different cancer cell lines. Analogue JA2 is the most potent analogue, and is currently undergoing in vivo testing at the NCI. In acute toxicity studies in non-tumor bearing mice, no overt toxicities were observed with analogue JA2 at dose up to 50 mg/kg i.p. Upon determining the HDAC inhibitory activity of the synthesized analogues using fluorimetric assay of recombinant HDAC1, HDAC2, HDAC3 and HDAC6, it was observed that analogues JA1 and JA2 inhibited Class I recombinant enzymes HDAC1, HDAC2 and HDAC3 significantly, while the Class II enzyme HDAC6 was relatively unaffected.JA2 is many fold more class selective than largazole.

Looking for partners:  To advance this technology and develop new HDAC inhibitors for treatment of various cancers.


1.     Taori, K.; Paul, V. J.; Luesch, H., Structure and activity of largazole, a potent antiproliferative agent from the Floridian marine cyanobacterium Symploca sp. J. Am. Chem. Soc. 2008, 130 (6), 1806-7 [Link]

2.     Bhansali, P.; Hanigan, C. L.; Casero, R. A.; Tillekeratne, L. M., Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: synthesis and biological evaluation. Journal of medicinal chemistry 2011, 54 (21), 7453-63 [Link]

3.     Bhansali, P.; Hanigan, C. L.; Perera, L.; Casero, R. A.; Tillekeratne, L. M. V., Synthesis and biological evaluation of largazole analogues with modified surface recognition cap groups. European Journal of Medicinal Chemistry 2014, 86, 528-541 [Link]

Patent Information:
For Information, Contact:
Katherine Pollard
Licensing Associate
The University of Toledo
Liyanaaratchige Tillekeratne
Ayad Al-Hamashi
Jehad Almaliti
Pravin Bhansali
Epigentic regulation
HDAC inhibitors