cancer-research-structural-biochemistry-2019-tracks

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Volume 3

August 5-6, 2019 | Singapore

CANCER RESEARCH AND PHARMACOLOGY

STRUCTURAL BIOCHEMISTRY, STEM CELLS AND MOLECULAR BIOLOGY

International Conference on

International Congress on

Cancer Research 2019 & Structural Biochemistry 2019

August 5-6, 2019

Journal of Cancer and Metastasis Research

Clin Psychol Cog Sci, Volume 3

Probing the mechanism of action of anti-AML heterocyclic diamidines

Van Ha

Georgia State University, USA

cute myeloid leukemia (AML) is associated with one of the top

mortalities among all the hematologic neoplasms. Chemotherapy

or radiotherapy alone, or with stem cell transplantation are current

treatment strategies. Due to dose-limiting myelosuppressive toxicity

and possible disease relapses after remission by chemotherapy,

an urgent AML therapeutic strategy is necessary to diminish the

tremendous human tolls of cancer. The ETS-family transcription factor

PU.1 plays a tumor suppressive role in many forms of AML and shows

depressed activity in leukemogenic stem cells. Recent studies have

shown that abolition of the residual PU.1 activity in low-PU.1 AML

terminates leukemia in patient cells and a mouse AML model. A small

molecules class known as heterocyclic diamidines had been designed and tested out as a target inhibitor of PU.1.

Understanding the physicochemical driving forces that confer high-affinity and selectivity is essential for the development

of therapeutic agents. To this end, we are investigating the DNA sequence selectivity of DB1976, one diamidine that shows

anti-AML activity

in vivo

, through its volumetric properties to site-specific and nonspecific binding. Volumetric measurements

complement calorimetric studies with more direct insights into hydration and dynamic properties of ligands-DNA interaction.

From volumetric measurements, we observed unexpectedly significant differences in volume change upon the formation of

DB1976 to each DNA sequences, suggesting correspondingly large differences in hydration or dynamics associated with

binding. Using explicit-solvent MD simulation, we detected the terminal base pairs of DNAs undergo transient opening events

and confirmed differential dynamics of sequence-dependent DNA manner in both bound and unbound state. This structural

feature allows us to correlate the stability of drug-DNA complexes with binding affinity and selectivity. This study suggested

that hydration and conformational dynamics play an equally important role as intermolecular contacts in contributing to the

mechanism of drug actions.

Biography

Van Ha graduated from Georgia State University with a Bachelor of Science in Chemistry (biochemistry concentration). She is currently

a research assistant in Dr. Gregory Poon’s lab at Georgia State University (GSU). She will start her Master study in Chemistry at GSU

in August 2019. She focuses on investigated hydration contributions to DNA selectivity of minor-groove binding ligand by high-precision

volumetric measurements; studied the cellular properties of designed DNA-targeting therapeutics

in vitro

; determined the affinity and

thermodynamics of transcription factor/DNA binding.