Chandanamali Punchihewa, PhD

Pharmaceutical Sciences
Drug Discovery and Development
Dissertation Title: 
“DNA and DNA-Interacting Proteins as Anticancer Drug Targets”

Year Graduated: 2006
Postdoctoral Fellow, St. Jude Childrens Research Hospital, Memphis, TN

Academic & Professional Updates
Advisor: Dr. Danzhou Yang
While at the University of Arizona, my research focused on DNA and DNA interacting proteins as anticancer drug targets. DNA is both the oldest and newest of targets for cancer therapy. A renewed interest in targeting DNA lies in the development of sequence-specific DNA binders. My studies on DNA interacting agents were initiated with the DNA intercalator campotothecin, and also included its target, topoisomerase I enzyme. I have evaluated the structure of topoisomerase I C-terminal domain that consists of the active site tyrosine. With regard to camptothecins, I have evaluated the DNA interactions of the camptothecin analogue homocamptothecin, and also the mechanism of topoisomerase I mediated inhibition of HIF-1 by camptothecin. In addition, I have also been involved with the determination of the mechanism of actionof another DNA binder, XR5944. Although shown to be a potent inhibitor of cell proliferation, its mechanism of action was not clearly identified. Our biochemical data, and the NMR structural data obtained in the lab, collectively show XR5944 to be an inhibitor of the DNA binding and the subsequent transcriptional activity of specific transcription factors. Focusing on DNA as a drug target, I have also studied specific secondary structures of DNA, the G-quadruplexes. Specifically I have analyzed the folding conformations of G-quadruplexes formed by human telomeric sequences.
I am currently working at the St Jude Children’s Research Hospital as a postdoctoral fellow. My research is focused on identification of inhibitors of protein-protein interaction in treatment of cancer. We target specific proteins in signaling pathways that are more active in cancer cells compared to normal cells. The interactions between different protein partners are investigated in order to rationally design inhibitors of such interactions. Subsequently, different chemical libraries are designed, synthesized and evaluated for their ability to specifically inhibit relevant protein interactions leading to cell apoptosis.

1. Liang You, Zhidong Xu, Chandanamali Punchihewa, David M. Jablons and Naoaki Fujii. Evaluation of a chemical library of small-molecule Dishevelled antagonists that suppress tumor growth by down-regulating T-cell factor–mediated transcription. Molecular Cancer Therapeutics (2008), 7(6): 1633-1638.
2. Neeraj Mahindroo, Chandanamali Punchihewa, Allison M. Bail and Naoaki Fujii. Indole-2-amide based biochemical antagonist of Dishevelled PDZ domain interaction down-regulates Dishevelled-driven Tcf transcriptional activity. Bioorganic & Medicinal Chemistry Letters (2008), 18: 946-949.
3. Jixun Dai, Megan Carver, Chandanamali Punchihewa, Roger A. Jones and Danzhou Yang. Structure of the Hybrid-2 type intramolecular human telomeric G-quadruplex in K+ solution: insights into structure polymorphism of the human telomeric sequence. Nucleic Acids Research, (2007) 35: 4927-4940.
4. Chandanamali Punchihewa
, Adrian De Alba, Neil Sidell, Danzhou Yang. XR5944: a potent inhibitor of estrogen receptors. Molecular Cancer Therapeutics (2007), 6(1): 213-219.
5. Chandanamali Punchihewa
, Jixun Dai, Megan Carver, Danzhou Yang. Human topoisomerase I C-terminal domain fragment containing the active tyrosine site is a molten globule: Implication for competent productive complex formation. Journal of Structural Biology (2007) 159(1): 111-21.
6. Jixun Dai, Chandanamali Punchihewa, Attila Ambrus, Ding Chen, R.A. Jones, Danzhou Yang. Structure of the intramolecular human telomeric G-quadruplex in potassium solution: a novel adenine triple formation. Nucleic Acids Research (2007) 35(7): 2440-50.
7. Jixun Dai, Chandanamali Punchihewa, Prakash Mistry, Aik Teong Ooi, Danzhou Yang. Novel DNA bis-intercalation by potent clinical anticancer bisphenazine drug MLN944. Journal of Biological Chemistry (2004) 279 (44): 46096-46103.
Originally posted: August 21, 2014
Last updated: October 8, 2015
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