Plenary Lecture 9

 



Title: Designing histone deacetylase (HDAC) inhibitors for use as CNS and cancer therapeutics – What’s easy and what’s not?

Professor Alan P. Kozikowski

University of Illinois at Chicago, USA
 

 

Lecture Summary: Histone deacetylases or HDACs are associated with the removal of acetyl groups from histones and a host of other proteins. Class I, II and IV HDACs require Zn2+ as a cofactor for their deacetylating activity and these are often referred to as the conventional HDACs. The sirtuins 1-7 are dependent on nicotinamide adenine dinucleotide for their activity and form class III of the HDACs. HDAC6 has garnished significant attention due to its unique structure and activity, and to the finding that HDAC6 knockout animals remain viable. While HDAC6 does not work on nuclear histones, it is involved in the acetylation status of proteins such as cortactin, HSF-1, HSP90, and tubulin. In particular, HDAC6 controls the acetylation status of the microtubule protein a-tubulin, and microtubule-dependent transport rates are more efficient along acetylated a-tubulin than deacetylated a-tubulin. This effect stems from the increased association of the motor proteins kinesin-1 and dynein with acetyl-tubulin, and therefore, affects both anterograde and retrograde transport activities. Thus, in addition to facilitating anterograde transport of new cargo to synaptic zones, acetyl-tubulin also increases the ability of damaged organelles or misfolded proteins to leave synaptic zones. This may be very important for Rett Syndrome as well as other disease conditions, as damaged mitochondria and elevated levels of improperly spliced mRNA transcripts have been noted in MeCP2-deficient neurons. In this lecture I will present information on the design, synthesis, and testing of ligands that are highly selective for HDAC6 inhibition and show how such compounds may find use as potential therapies in diseases such as Rett syndrome, Alzheimer’s disease, cancer, stroke, and CMT.


Acknowledgments:
We are indebted to the National Instititues of Health (NS079183) for their support of our HDAC program.

References: 1. Wang Z, Leng Y, Wang J, Liao HM, Bergman J, Leeds P, Kozikowski A, Chuang, DM, Tubastatin A, an HDAC6 inhibitor, alleviates stroke-induced brain infarction and functional deficits: potential roles of α-tubulin acetylation and FGF-21 up-regulation. Sci Rep. Sci Rep. 2016 Jan 21;6:19626. doi: 10.1038.

2. d'Ydewalle, C.; Krishnan, J.; Chiheb, D. M.; Van Damme, P.; Irobi, J.; Kozikowski, A. P.; Vanden Berghe, P.;  Timmerman, V.; Robberecht, W.; Van Den Bosch, L. (2011), HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nature Medicine, 17, 968-974. PMID: 21785432.

3. Sida Shen, Veronick Benoy, Joel A. Bergman, Jay H. Kalin, Mariana Frojuello, Giulio Vistoli, Wanda Haeck, Ludo Van Den Bosch,and Alan P. Kozikowski, Bicyclic-capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot-Marie-Tooth Disease. ACS Chem Neurosci. 2016 Feb 17;7(2):240-58. doi: 10.1021.