Activators of the Anticipatory Unfolded Protein Response with Enhanced Selectivity for Estrogen Receptor Positive Breast Cancer

Abstract

Approximately 75% of breast cancers are estrogen receptor alpha-positive (ERα+), and targeting ERα directly with ERα antagonists/degraders or indirectly with aromatase inhibitors is a successful therapeutic strategy. However, such treatments are rarely curative and development of resistance is universal. We recently reported ErSO, a compound that induces ERα-dependent cancer cell death through a mechanism distinct from clinically approved ERα drugs, via hyperactivation of the anticipatory unfolded protein response. ErSO has remarkable tumor-eradicative activity in multiple ERα+ tumor models. While ErSO has promise as a new drug, it has effects on ERα-negative (ERα−) cells in certain contexts. Herein, we construct modified versions of ErSO and identify variants with enhanced differential activity between ERα+ and ERα– cells. We report ErSO-DFP, a compound that maintains antitumor efficacy, has enhanced selectivity for ERα+ cancer cells, and is well tolerated in rodents. ErSO-DFP and related compounds represent an intriguing new class for the treatment of ERα+ cancers.

Evolution of 3-(4-hydroxyphenyl)indoline-2-one as a scaffold for potent and selective anticancer activity

“…This increase in selectivity in cell culture also translated to an increase in the tolerability seen with in vivo preclinical models, namely significant increases in the maximum tolerated doses (MTD) of ErSO-DFP in mice and rats with >3 fold increases in tolerability in both species. As mentioned previously, ErSO shows a similar speciation toxicity in rats 111,126 to that of compound other 3-(4-hydroxyphenyl)indoline-2-ones. 109 In contrast, ErSO-DFP is well-tolerated in rats up to its solubility limit.…”

“…ErSO-DFP 's lipophilic efficiency (LipE) is 3.4, a >2 unit increase when compared to progenitor ErSO (LipE: 1.3). 126 Importantly, ErSO-DFP maintains an ERα-dependent activity with an often >2000 fold difference between activity seen against ERα-positive and ERα-negative cancer cell lines (Fig. 3).…”

“…As such, while preclinical evidence suggests ErSO holds tremendous translational promise, we undertook a campaign to discover derivatives that have: (1) enhanced selectivity for ERα+ cancer cells in culture, (2) maintain ErSO 's remarkable ability to eradicate tumors in vivo , and (3) have wider therapeutic windows in vivo . 126 Notably, these ‘second generation’ compounds would also be better positioned as chemical probes for studying the underlying biological mechanism ( e.g. a-UPR) that is leading to the profound antitumor responses.…”

“…This pursuit of decreasing lipophilicity led to the design and synthesis of nitrogen heterocycle-containing derivatives with clog D 7.4 values ranging from 2.6 to 4.9 (Scheme 11). 126 One of the most intriguing of this set of compounds was a 4,4-difluoropiperidine containing derivative, ErSO-DFP (Scheme 11), with a clog D 7.4 of 4.4. The importance of this difluorination on anticancer efficacy is clear, as variants lacking these fluorine atoms were devoid of activity.…”

“…The importance of this difluorination on anticancer efficacy is clear, as variants lacking these fluorine atoms were devoid of activity. 126…”