Translational development and mechanistic insights into 3-(4- hydroxyphenyl)indoline-2-ones as a potent class of breast cancer therapeutics

Mulligan, Michael Patrick

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https://hdl.handle.net/2142/132726 Copy

Description

Title

Translational development and mechanistic insights into 3-(4- hydroxyphenyl)indoline-2-ones as a potent class of breast cancer therapeutics

Author(s)

Mulligan, Michael Patrick

Issue Date

2025-09-08

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

Hergenrother, Paul

Doctoral Committee Chair(s)

Hergenrother, Paul

Committee Member(s)

• Fan, Timothy
• van der Donk, Wilfred
• Jun, Joomyung

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Medicinal Chemistry
• Breast Cancer, Therapeutic, Target Identification

Abstract

Cancer research and therapy have seen major developments in recent decades with the paradigm of surgery/radiotherapy/chemotherapy advancing towards selective small molecules, biologics, immunotherapy, and other targeted therapies. Small molecule drug development remains an important cornerstone of the field with the discovery and optimization of new chemical scaffolds often driving insights in disease-relevant biology. 3-(4-hydroxyphenyl)indoline-2-ones are a class of compounds that exhibited potent biological activity for decades, but little was known regarding the mechanism of action. Oxyphenisatin acetate, a founding member of this class, was used as a laxative in the 1960’s, and in subsequent decades was found to have antiproliferative activity against cancer cells. Research on this scaffold in the Hergenrother lab has focused on the optimization of derivatives for anticancer activity, preclinical progression of promising molecules, and target identification efforts to better understand the biology behind this scaffold’s activity. Herein we report our efforts to synthesize 3-(4-hydroxyphenyl)indoline-2-one derivatives with improved selectivity and tolerability which has resulted in a number of novel compounds, a better understanding of structure-activity relationship surrounding the scaffold, and the discovery of several promising small molecules including ErSO-DFP and ErSO-TFPy. The lipophilicity and stability of these compounds appear to be key parameters determinant of antiproliferative activity and selectivity between cancer cell lines. Importantly, these derivatives are well tolerated across animal models and demonstrate impressive activity in preclinical models for breast cancer. ErSOTFPy was found to be capable of inducing complete regressions in murine xenografts following a single dose, a very unusual and promising attribute for translational development. Our efforts to identify the biological target have revealed the importance of TRPM4, a calcium activated ion channel, to the anticancer activity of these derivatives and this scaffold. Our research suggests that TRPM4 is a direct biological target of this class of molecule, but more evidence of direct binding is being sought for conclusive proof. The significance of this discovery and its relevance to translational development of 3-(4-hydroxyphenyl)indoline-2-ones is still unclear. However, this new information regarding the mechanism of action lays the foundation for optimization of newer derivatives and a more complex understanding of the biology governing the activity of this scaffold.

Graduation Semester

2025-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/132726

Copyright and License Information

Copyright 2025 Michael Mulligan

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