Anticancer compounds selective for ER-positive cancers
Inventors
Hergenrother, Paul J. • BOUDREAU, Matthew
Assignees
Illinois Urbana Illinois, University of, Trustees of • University of Illinois System
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Publication Number
US-12655104-B2
Publication Date
2026-06-16
Expiration Date
Abstract
Small molecule ERα biomodulators that kill therapy-resistant ERa positive breast, ovarian, and endometrial cancer cells are disclosed. In one embodiment, the small molecule biomodulator has increased therapeutic utility because of an increased ability to kill therapy-resistant cancer cells compared to BHPI and other conventional therapies (endocrine therapies, tamoxifen, and fulvestrant/ICI). The small molecule biomodulators not only inhibit proliferation of the cancer cells but kills them, which prevents reactivation of tumors years later. Compounds of the invention, such as ErSO-DFP, are effective for treating ERa positive cancers such as breast cancer, ovarian cancer, uterine cancer, cervical carcinoma, endometrial cancer, and the like.
Core Innovation
The invention relates to compounds of Formula I, and pharmaceutically acceptable salts thereof, including compounds such as ErSO-DFP. The compounds are described as small-molecule ERα biomodulators that selectively target ERα+ cells, including therapy-resistant ERα+ breast and related cancers, by promoting hyperactivation of the anticipatory unfolded protein response (a-UPR).
The disclosed compounds are directed to therapy-resistant ERα+ breast and related cancers, where a cytoprotective ERα pathway contributes to tumor survival. The patent links the compounds to anti-tumor activity in ERα-positive cancer contexts and describes medicinal-chemistry exploration of phenolic (Ring A) and amine-containing (Ring B) modifications to achieve and control the ERα-selective cytotoxic effect.
A structural scope for compounds of Formulas I–III is disclosed, including a general scaffold with variable heteroatom substitutions and a benzylic attachment to N-containing heterocycles such as difluorinated piperidines/pyrrolidines. The document further reports salts and stereochemistry options, example indolin-2-one analogs, and that minor phenol-ring changes can abrogate activity while difluorinated piperidine-containing heterocycles maintain potent activity.
Claims Coverage
The independent claims include a compound claim covering a defined Formula I scaffold, including salts, and a method of treating ERα-positive cancer by administering such compounds. In total, the provided claims center on 2 inventive features.
Formula I ERα biomodulator compound
A compound of Formula I, wherein X is O, S, or NRa; Y is NRa, O, or S; each Ra is independently H or alkyl; R1 is alkyl, cycloalkyl, halo, −ORb, −SRb, or −N(Rb)2 with allowed optional substitution; R2, R3, and R4 are each independently H, trifluoromethyl, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, halo, −ORb, −SRb, or −N(Rb)2; each Rb is independently H, trifluoromethyl, or alkyl; each Rx is independently OH, halo, alkyl, −ORc, −SRc, or −S(=O)2Rc; each Rc is independently H, trifluoromethyl, or alkyl; n is 1, 2, 3, 4, 5, or 0; and Z is a 6-, 5-, 4-, 7-, or 8-membered nitrogen-containing heterocycle bonded via a nitrogen atom to the benzylic carbon atom of Formula I and substituted with one or more substituents; or a salt thereof.
Treating ERα-positive cancer by administering Formula I compound
A method for treating an ERα-positive cancer by administering to a subject with the ERα-positive cancer a therapeutically effective amount of the compound of Formula I (as defined in the compound claim), thereby treating the cancer.
Overall claim coverage centers on the Formula I ERα biomodulator scaffold with defined heteroatom selections, substituent classes, and a bonded nitrogen-containing heterocycle Z, including salts, together with use of the Formula I compound to treat ERα-positive cancer by administering a therapeutically effective amount.
Stated Advantages
Lower cLogD7.4 relative to bis-aryl analogs is reported for the ring B fluorinated derivatives.
Potent ERα-dependent anticancer activity is reported for 4,4-difluoropiperidine-containing compounds.
Enantioselectivity is reported, with the (R)-enantiomer being active and the (S)-enantiomer inactive.
Compounds lacking the 4,4-difluoro motif show little or no activity.
Reduced ERα-independent killing is reported for certain derivatives assessed across additional ERα− cancer cell lines.
Improved therapeutic window and ERα+ tumor regression are reported in an MCF-7 xenograft model.
Improved selectivity for ERα+ versus ERα− cells.
Improved lipophilic efficiency and in vivo tolerability.
Activation of the anticipatory unfolded protein response (a-UPR).
Strong antitumor tumor regression in ERα+ murine models.
A wider therapeutic window at low dose.
Documented Applications
Evaluation of Ring B fluorinated nitrogen-containing derivatives via SAR and biological evaluation in cellular assays including MCF-7 cells and additional cancer cell lines in ERα+ and ERα− contexts, with reported IC50 values and metrics such as LipE/cLogD.
Mechanistic characterization reporting a-UPR activation, including western blots and associated pathway markers, for the fluorinated derivatives.
In vivo use as a mouse pharmacokinetic/tolerability and head-to-head comparison study for ErSO-DFP versus ErSO, including reporting PK parameters and maximum tolerated dose (MTD).
In vivo anticancer application in an MCF-7 xenograft tumor model reporting ERα+ tumor regression and therapeutic index/therapeutic window.
Simulated gastric fluid stability assessment for representative derivatives to report stability half-lives and remaining fraction.
Treatment of ERα-positive cancers by administering a therapeutically effective amount of a Formula I compound to a subject with the ERα-positive cancer.
Tumor types treated include breast, ovarian, uterine, cervical, endometrial, and others as described in the document.
Use in pharmaceutical formulations and unit dosage forms, including tablets, capsules, injection, aerosol, topical gel, topical ointment, and topical cream, with pharmaceutically acceptable salts and multiple routes of administration as described in the partial content.
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