Cytotoxic agents that preferentially target leukemia inhibitory factor (LIF) for the treatment of malignancies and as new contraceptive agents
Inventors
Nair, Hareesh • Santhamma, Bindu • Nickisch, Klaus
Assignees
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Publication Number
US-10738075-B2
Publication Date
2020-08-11
Expiration Date
Abstract
Described herein are new anti-cancer compounds and methods of using such compounds, acting through a new mechanism of action by simultaneous inhibition of leukemia inhibitory factor (LIF) and MDM2.
Core Innovation
The invention relates to an anti-cancer cytotoxic small-molecule class that simultaneously inhibits leukemia inhibitory factor (LIF) or LIFR and MDM2. Downstream effects include inhibition of STAT3 phosphorylation and stabilization of p53, and the disclosure frames these compounds as acting through defined molecular targets rather than a single pathway.
The problem being addressed is the treatment of cancers, including those associated with overexpressing LIF and a desmoplastic stromal response. The disclosure also connects the therapeutic context to stem-cell populations, including cancer initiating stem cells (CISC) and cancer associated stem cells (CASC), and associates the stromal context with carcinoma-associated fibroblasts (CAF) and hypertrophic fibroblasts.
The document also describes cytotoxic compounds having a defined estrane-based structure, including estra-4,9-dien-3-one features, with a difluoro propargyl motif and varied 11β-aryl substituents. It includes described transformations, intermediates, and characterization data, and it states that structures and transformations are confirmed by spectroscopic methods including UV, FT IR, 1H NMR, and 13C NMR.
Claims Coverage
The identified claim coverage centers on cytotoxic compounds of structure (III)/(IV). The inventive features are the defined structural framework, fixed F substituents at R2 and R3, limited choices for R4 and R6, and a heterocycle requirement for R5 with dependent narrowing to named heterocycles.
Cytotoxic compound having structure (III) with R2 and R3 as F
A cytotoxic compound having the structure (III), where R2 and R3 are F.
Cytotoxic compound having structure (III) with defined R4 substituents
A cytotoxic compound having the structure (III), where R4 is H, alkyl, —CH2—OH, —CO2R6, or —CON(R6)2.
Cytotoxic compound having structure (III) with R5 as a heterocycle
A cytotoxic compound having the structure (III), where R5 is a heterocycle.
Cytotoxic compound having structure (III) with defined R6 substituents
A cytotoxic compound having the structure (III), where R6 is H, alkyl, or cycloalkyl.
Cytotoxic compound with specified heterocycle for R5
The cytotoxic compound of structure (IV) in which R5 is one of quinolinyl, isoquinolinyl, indolyl, 1,3-imidazolyl, dibenzofuranyl, or furanyl.
Cytotoxic compound with R5 as named heterocycles
The cytotoxic compound of structure (IV) in which R5 is quinolinyl, 1,3-imidazolyl, or dibenzofuranyl.
The claim coverage is centered on a defined cytotoxic compound structure (III)/(IV) with R2 and R3 as F, R4 selected from a limited group of substituent types, R5 required to be a heterocycle and narrowed in dependent variants to named heterocycles, and R6 selected from H, alkyl, or cycloalkyl.
Stated Advantages
Strong, dose-dependent cytotoxicity in NCI-60 and cancer cell lines.
Low-nanomolar IC50 values for example compounds such as EC330/EC332.
Inhibition of colony and tube formation (anti-angiogenic effects).
Modulation of LIF/STAT3 signaling, including reduced pSTAT3.
Restoration of p53 via reduced MDM2.
Inhibition of xenograft tumor burden in described xenograft models.
Cell specificity associated with LIF-overexpressing cells.
Proposed contraceptive use via LIF inhibition during implantation.
Inhibits leukemia inhibitory factor (LIF) or LIFR and MDM2 simultaneously.
Inhibits STAT3 phosphorylation.
Stabilizes p53.
Documented Applications
Use of the disclosed cytotoxic compounds in cancer contexts, including cytotoxicity testing in the NCI-60 panel and cancer cell lines, and xenograft tumor burden reduction in described xenograft models.
Anti-angiogenic effects described via inhibition of HUVEC tube formation and related assays.
Use related to implantation and contraceptive purposes through LIF inhibition during implantation, including mention of decidualization assay context and LIF specificity assay statements.
Therapeutic methods for treating cancers overexpressing LIF/desmoplastic stroma and related stem-cell populations, including cancer initiating stem cells (CISC) and cancer associated stem cells (CASC).
Companion-diagnostic selection by monitoring STAT3 phosphorylation downregulation.
Contraceptive use as contraceptive agents.
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