The development of 3-(4-hydroxyphenyl)indoline-2-ones and other strategies for the treatment of cancer

Over the past century, our ability to develop new targeted anticancer strategies has ushered in a new era in cancer treatment that has greatly evolved from the radical surgery and highly toxic campaigns of the past. Often common in anticancer small molecule development is a complex history outlining how chemical matter was first identified, derivatized, and utilized to ultimately arrive at exciting molecules for drug development. Herein, the history and our current journey of one such developing anticancer scaffold, the 3-(4-hydroxyphenyl)indoline-2-ones, is reviewed. With humble beginnings in 19th century Bavaria to recent interest in its tumor eradication of drug-resistant breast cancer, 3-(4-hydroxyphenyl)indoline-2-ones are an intriguing anticancer pharmacophore. Specifically, we describe our discovery of ErSO, a 3-(4-hydroxyphenyl)indoline-2-one that induces estrogen receptor alpha-positive (ERα)-dependent death of breast cancer cells through a mechanism distinct from clinically approved ERα drugs, namely hyperactivation of the anticipatory unfolded protein response (a-UPR). ErSO has remarkable activity in multiple ERα-positive tumor models, with several examples of complete tumor eradication without recurrence. While ErSO has tremendous promise as a new drug to target ERα-positive breast cancer, we also report herein the discovery of second-generation derivatives, ErSO-DFP and ErSO-TFPy, which have even more promising targeted anticancer activities. Unrelated to 3-(4-hydroxyphenyl)indoline-2-ones research, a variety of other ongoing anticancer projects being developed in the Hergenrother laboratory (PAC-1 and IB-DNQ) are described.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Boudreau, Matthew W.

Contributors dc:contributor

• Hergenrother, Paul J
• Burke, Martin D
• Mitchell, Douglas A
• Fan, Timothy M

• cancer
• drug development

Statement dc:rights

• Copyright 2022 Matthew W. Boudreau

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/115658

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F115658