Potent anticancer activity via dual compound activation
Inventors
Hergenrother, Paul J. • Botham, Rachel C. • Fan, Timothy M. • Gilbert, Mark J. • HANDLEY, Michael K. • Tarasow, Theodore M.
Assignees
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Publication Number
US-9592229-B2
Publication Date
2017-03-14
Expiration Date
Abstract
The invention provides compositions and methods for the induction of cell death, for example, cancer cell death. Combinations of compounds and related methods the use are disclosed, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells. The disclosed drug combinations can have lower neurotoxicity effects than other compounds and combinations of compounds.
Core Innovation
The disclosure describes an anticancer strategy using a dual activation concept directed to the apoptosis effector procaspase-3. A composition is provided that includes a compound of Formula (I) wherein R is H or Me, the compound PAC-1, and a pharmaceutically acceptable diluent, excipient, or carrier. PAC-1 potentiates procaspase-3 activation to caspase-3, thereby driving apoptosis.
The disclosure frames the problem as inducing apoptosis in cancer cells through caspase activation while addressing mechanistic distinctness and safety considerations. It states that apoptosis is caspase-dependent and references inhibition by Q-VD-OPh. It further states that procaspase-3 expression is required, including a minimal effect in MCF-7 lacking procaspase-3.
The disclosure also describes that the combination can produce synergy, specifically that 1541/1541B and PAC-1 act via distinct mechanisms. This results in increased DEVDase/caspase-3 activity and rapid procaspase-3 maturation in multiple cancer cell lines. In vivo support is provided in an EL4 murine tumor model, where PAC-1 plus 1541B markedly retards tumor growth compared with single agents.
Claims Coverage
The independent claims cover four total aspects: a pharmaceutical composition, a method of potentiating compound activity toward cancer cells, a method of inducing apoptosis in cancer cells, and a method of therapeutically treating specified cancers in a patient using concurrent or sequential administration. Together they define a combination of a compound of Formula (I) wherein R is H or Me with PAC-1, and they connect use to apoptosis and anticancer outcomes.
Pharmaceutical composition of formula (I) plus PAC-1
A composition comprising a compound of Formula (I) wherein R is H or Me, the compound PAC-1, and a pharmaceutically acceptable diluent, excipient, or carrier.
Potentiating formula (I) activity with PAC-1 toward cancer cells
A method of potentiating the activity of a compound of Formula (I) wherein R is H or Me, comprising contacting a cancer cell with a combination of the compound of Formula I and an effective activating amount of PAC-1, wherein the PAC-1 potentiates the activity of the compound of Formula (I) toward the cancer cell.
Inducing apoptosis by contacting with formula (I) and PAC-1
A method of inducing apoptosis in a cancer cell comprising contacting the cancer cell with an effective amount of a compound of Formula (I) wherein R is H or Me, and an effective amount of the compound PAC-1, wherein apoptosis is thereby induced in the cancer cell.
Therapeutic treatment of breast cancer, leukemia, or lymphoma with concurrent or sequential administration
A method of inhibiting cancer, arresting cancer, relieving cancer, reversing the progression of cancer, reversing the severity of cancer, and/or therapeutically treating cancer in a patient in need thereof comprising administering to the patient, concurrently or sequentially, a therapeutically effective amount of a compound of Formula (I) wherein R is H or Me, and an effective amount of the compound PAC-1, wherein the cancer is breast cancer, leukemia, or lymphoma.
Overall claim coverage ties a pharmaceutical composition of Formula (I) plus PAC-1 to methods that potentiate Formula (I) activity toward cancer cells, induce apoptosis in cancer cells by contacting with both agents, and therapeutically treat specified cancers in patients using concurrent or sequential administration.
Stated Advantages
PAC-1 potentiates procaspase-3 activation to caspase-3, thereby driving apoptosis.
The combination produces synergy with increased DEVDase/caspase-3 activity and rapid procaspase-3 maturation.
Apoptosis is caspase-dependent.
Procaspase-3 expression is required for effect, with minimal effect in MCF-7 lacking procaspase-3, supporting selectivity related to procaspase-3 targeting.
In vivo, PAC-1 plus 1541B markedly retards tumor growth versus single agents in an EL4 murine tumor model.
Potential reduced neurotoxicity/greater selectivity is stated due to targeting procaspase-3 overexpressed in tumors.
Documented Applications
Inducing apoptosis in a cancer cell by contacting with an effective amount of a compound of Formula (I) wherein R is H or Me and an effective amount of PAC-1.
Potentiating the activity of a compound of Formula (I) toward a cancer cell by contacting the cancer cell with a combination of the Formula (I) compound and an effective activating amount of PAC-1.
Therapeutically treating a patient in need thereof for cancer including breast cancer, leukemia, or lymphoma by administering a therapeutically effective amount of a compound of Formula (I) wherein R is H or Me and an effective amount of PAC-1, concurrently or sequentially.
In vivo use supported in an EL4 murine tumor model where PAC-1 plus 1541B retards tumor growth compared with single agents.
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