Compositions to improve the therapeutic benefit of bisantrene and analogs and derivatives thereof
Inventors
Garner, William J. • FRANKLIN, Amie • Rothman, John
Assignees
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Publication Number
US-9993460-B2
Publication Date
2018-06-12
Expiration Date
Abstract
The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutic agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to bisantrene or derivatives, analogs, or prodrugs thereof.
Core Innovation
The invention concerns bisantrene and bisantrene analogs and derivatives as G-quadruplex-interacting agents that act to produce telomerase/telomere dysfunction. The described mechanism involves recognition of G-quadruplex structures through protonatable amine side chains, followed by disruption of the telomere-telomerase functional relationship, impaired telomere-telomerase interaction, and senescence.
The described mechanism further includes displacement of TRF2 and hPOT1 from telomeric regions, which is linked to activation of a DNA damage response. The document associates these events with senescence pathway markers including γH2AX foci and p21Waf1, and with senescence-associated β-galactosidase. Overall, the invention frames bisantrene and derivatives as causing G-quadruplex-dependent telomeric perturbation that leads to dysfunction and senescence.
The document also describes structural exemplars of bisantrene analogs and derivatives, including Formula (IX) HL-37 and additional analog sets such as Formulas (X)-(XIII), as well as diphosphoramidic and monophosphoramidic derivatives described by Formula (XIV). The variants are defined using substituent classes and optional substitutions for a bisantrene derivative scaffold, including a general B(Q)n schematic.
Claims Coverage
Two independent claims are present. The shared inventive constraint is a therapeutically effective bisantrene composition intended to improve efficacy and/or reduce side effects in suboptimally administered drug therapy, with treatment limited to specified malignancies and delivery via either a drug conjugate form or a prodrug system.
Drug conjugate form for bisantrene in a suboptimal-therapy composition
A composition comprising a therapeutically effective quantity of bisantrene for treatment of a malignancy, where the composition provides increased therapeutic efficacy or reduced side effects for suboptimally administered drug therapy, and where bisantrene is included in a drug conjugate form selected from polymer systems, polylactides, polyglycolides, amino acids, peptides, multivalent linkers, fatty acid or fatty alcohol conjugates, elastin-like peptide conjugates, conjugates with antibodies, proteins, or peptides, conjugates with cell-binding agents through a charged or pro-charged cross-linker, antibodies targeted to tumor markers, biodegradable polymer-bioactive moiety conjugates, 2-nitroimidazole conjugates, ladder frame polyether conjugates, activatable antibodies with masking and cleavable moieties, antibodies specific for interleukin-6, p97-targeting conjugates, and other listed conjugate types.
Prodrug system for bisantrene in a suboptimal-therapy composition
A composition comprising a therapeutically effective quantity of bisantrene for treatment of a malignancy, where the composition provides increased therapeutic efficacy or reduced side effects for suboptimally administered drug therapy, and where the composition includes a prodrug system selected from enzyme sensitive esters, dimers, Schiff bases, pyridoxal complexes, caffeine complexes, plasmin-activated prodrugs, drug targeting complexes with selectively distributed targeting carrier and linker acted upon by a molecule present at an effective concentration in the environs of a specific cell type, and a prodrug molecule comprising a conjugate of bisantrene, a protease-specific cleavable peptide, optionally a targeting peptide, wherein the prodrug molecule is substantially inactive prior to degradation of the protease-specific cleavable peptide by a proteolytic enzyme within or in close proximity to the cancer cell.
Across both independent claims, the core limitation is a bisantrene-containing composition for suboptimally administered drug therapy that improves therapeutic efficacy and/or reduces side effects for specified malignancies, with the additional inventive constraint being either a listed drug conjugate form or a listed prodrug system.
Stated Advantages
Increased therapeutic efficacy for treatment of a malignancy.
Reduced side effects of suboptimally administered drug therapy.
Documented Applications
Treatment of refractory breast cancer.
Treatment of ovarian cancer.
Treatment of breast cancer characterized by overexpressed Her-2-neu.
Treatment of triple-negative breast cancer.
Treatment of acute myelocytic leukemia.
Treatment of acute leukemias of childhood.
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