AZ505 [N-cyclohexyl-3-(3,4-dichlorophenethylamino)-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b]
[1,4]oxazin-8-yl)ethylamino)ethyl)propanamide], is a potent and highly
selective inhibitor of SMYD2 (SET and MYND domain-containing protein) with an
IC50 value of 0.12 uM. Moreover, AZ505 failed to inhibit the
enzymatic activities of a panel of protein lysine methyltransferases. It is
highly selective for SMYD2, with respect to other members such as SMYD3, DOT1L,
EZH2, GLP, G9A and SET7/9, all having IC50 values greater than 80
uM [1].
The activity of AZ505 is as follows:
IC50 (SMYD2 enzyme assay) = 0.12 uM;
Common Name: AZ505
Synonyms: AZ505;
AZ-505; AZ 505
IUPAC Name: N-cyclohexyl-3-(3,4-dichlorophenethylamino)-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b]
[1,4]oxazin-8-yl)ethylamino)ethyl)propanamide
CAS Number: 1035227-43-0
SMILES: O=C1COC2=C(CCNCCN(C3CCCCC3)C(CCNCCC4=CC(Cl)=C(Cl)C=C4)=O)C=CC(O)=C2N1
Mechanism of Action: Lysine
Methyltransferases Inhibitor; SMYD2 Inhibitor
Indication: Various
Cancers
Development Stage: Investigational
Company: AstraZeneca
The human SMYD
(SET and MYND domain-containing protein) family of protein lysine
methyltransferases contains five members (SMYD1-5) and their defined roles in
development of cancer have been established. For example, disruption of SMYD1
leads to perturbed cardiac morphogenesis and embryonic lethality, whereas SMYD3
has been shown to be involved in cancer cell proliferation, and is
overexpressed in hepatocellular, colorectal, and breast carcinomas.
SMYD2 has been
shown to methylate both histone (H2B, H3, and H4) and nonhistone protein
substrates, including the tumor suppressor proteins p53 and Rb. In addition to
these established biological pathways, the SMYD2 gene lies in the 1q32- q41
region, which is frequently amplified in esophageal squamous cell carcinoma
(ESCC) and other solid tumors. Overexpression of SMYD2 is observed in the
esophageal cell line KYSE150, and in ESCC primary tumor samples. Genetic
knockdown of SMYD2 leads to decreased ESCC cell proliferation [1]. Hence, SMYD2
appears to be a valid target for ESCC treatment.
Based upon
experimental data such as change in heat of formation, entropy etc, it is
hypothesized that AZ505 binding to SMYD2 is driven primarily by entropy, which
often suggests that binding is mediated by hydrophobic interactions with few
specific hydrogen bonds. Analysis of the double-reciprocal plot of the initial
velocities against substrate concentrations indicates that AZ505 binding to
SMYD2 is competitive with the peptide substrate and uncompetitive with the
cofactor.
References:
1. Ferguson, A. D.; et. al. Structural basis of substrate methylation and inhibition of
SMYD2. Structure 2011, 19(9), 1262-1273.
