The discovery of small molecule inhibitors of poly(ADP-ribose) mediated cell death

Finch, Kristin E.

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Description

Title

The discovery of small molecule inhibitors of poly(ADP-ribose) mediated cell death

Author(s)

Finch, Kristin E.

Issue Date

2011-05-25T14:39:30Z

Director of Research (if dissertation) or Advisor (if thesis)

Hergenrother, Paul J.

Doctoral Committee Chair(s)

Hergenrother, Paul J.

Committee Member(s)

• Burke, Martin D.
• Rienstra, Chad M.
• Oldfield, Eric

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• poly(ADP-ribose) glycohydrolase (PARG)
• Poly(ADP-ribose) polymerase (PARP)
• poly(ADP-ribose) (PAR)
• Rhodanines
• small molecule inhibitors

Abstract

The emergence of resistance to cancer treatments through methods that generate cell death by inducing DNA damage, such as chemotherapeutics and radiation therapy, is a major obstacle to overcoming the disease. Resistance occurs through the repair of single strand DNA breaks by the poly(ADP-ribose) (PAR) cycle, which is an enzymatic cycle that promotes DNA repair after mild DNA damage. In contrast, upon severe DNA damage, the PAR cycle is known to promote acute cell death, which can result in ischemia or neurological diseases. Therefore, proteins in this pathway are being studied as potential pharmacological targets for cancer and ischemic events. Poly(ADP-ribose) polymerase-1 (PARP-1), the enzyme that synthesizes PAR, inhibitors are currently in clinical trials as chemopotentiators, and as personalized treatments for patients with the BRCA-1/-2 mutation. However, there is a lack of small molecule inhibitors of other important enzymes and proteins in this pathway. Therefore, described herein is the discovery and evaluation of small-molecule inhibitors of poly(ADP-ribose) glycohydrolase (PARG), the enzyme that degrades PAR, and apoptosis inducing factor (AIF), a protein that orchestrates stage I chromatin condensation. Recognizing that the phosphate moiety, which is cell impermeable, is necessary for PARG recognition and binding, Chapter 2 describes how small molecules containing the rhodanine motif, a known phosphate replacement, were screened for PARG inhibition in hopes of discovering a cell permeable inhibitor of PARG. A compound was identified as a PARG inhibitor, and upon derivative synthesis, its properties were optimized to improve potency (IC50 <10 uM) and solubility. After analyzing compound specificity, the rhodanine-containing PARG inhibitors were tested in both cell lysate and cell culture to assess their ability to inhibit PARG in complex environments. In Chapter 3, compounds that prevented the ability of AIF to bind DNA were identified and chemically optimized. Although, the inhibitors of AIF proceeded with less success, the identified compounds were used in a proof-of-concept analysis of photonic crystal biosensors to identify aggregating compounds, and as a novel and facile mechanism to label proteins.  

Graduation Semester

2011-05

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http://hdl.handle.net/2142/24355

Copyright and License Information

Copyright 2011 Kristin E. Finch

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