Tuesday, June 9, 2015

Drugs in Clinical Pipeline: AZ505

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; Kd = 0.5 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
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.


1.    Ferguson, A. D.; et. al. Structural basis of substrate methylation and inhibition of SMYD2. Structure 2011, 19(9), 1262-1273.