1. Anticancer Agents
Lecture 6
Dr. Jehad Almaliti

2. Introduction
• Healthy cells are under strict
biochemical control for growth and
differentiation.
• In cancer, these regulatory processes
have gone awry, and cells grow and
divide uncontrollably
• Class of anticancer agents:
• DNA cross-linking agents (Nitrogen
mustards)
• Antimetabolites
• Protein tyrosine kinase inhibitors
• Histone deacetylase inhibitors

3. Histones are packing material for DNA!
• In chromatins, DNA is wrapped around proteins
of which most are histones.
• Histones assist in DNA packaging and have a
regulatory role.
• Histones have a high proportion of positively
charged amino acids (lysine and arginine) which
bind tightly to the negatively charged DNA.
• Four core histones H2A, H2B, H3, and H4 serve
to wrap DNA into nucleosomes.
• Nucleosomes is the repeating pattern of 8
histone proteins along the length of the
chromatin structure, with each octet associated
with 146 basepairs of DNA
• The linker histone H1 role

4. Histone Acetylation and Decatylaion
• Histone acetylation regulated by 2 protein families:
 Histone acetyltransferase (HAT)
 Histone deacetylase (HDAC)
o HDACs classified into:
 Class I: HDAC 1, 2, 3, and 8 reside in nucleus
 Class IIa: HDAC 4, 5, 7 and 9 shuttle between nucleus and cytoplasm
 Class IIb: HDAC 6 and 10 shuttle between nucleus and cytoplasm
 Class III: sirtuin protein, consists of 7 types of protein
 Class IV: HDAC11 shuttles between nucleus and cytoplasm
H
N
O
H
N
O
H
N
O
NH3
HDAC
HAT

5. www.ifom-ieo-campus.it/research/chiocca.php

6. Hydroxamic acid
• First compound to be identified as HDAC inhibitors
• suberoyl anilide hydroxamic acid (SAHA)

8. Binding of SAHA to HDAC

9. FDA approved HDAC inhibitors

10. Natural product HDACi
Taori, K. ; Paul V. J.; Luesch H. J., Am. Chem. Soc. 2008, 130, 1806-1807