SMAC mimetic
Inventors
Condon, Stephen M. • Deng, Yijun • Laporte, Matthew G. • Rippin, Susan R.
Assignees
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Publication Number
US-11951147-B2
Publication Date
2024-04-09
Expiration Date
Abstract
A SMAC mimetic and pharmaceutical compositions thereof and methods of use.
Core Innovation
The disclosed invention relates to a SMAC mimetic lead compound designated as Compound 15, including pharmaceutically acceptable salts and forms. Compound 15 is defined by a detailed chemical structure in which R5 is CH2CH3, and the disclosure characterizes the compound as a SMAC mimetic.
The invention addresses treatment of proliferative disorders, notably cancers, by inducing apoptosis through IAP antagonism. The disclosure frames the mechanism in terms of SMAC/DIABLO antagonizing IAPs, including XIAP, cIAP-1, cIAP-2, and ML-IAP, to promote apoptotic activity, and further situates the approach within apoptosis-related conditions beyond cancer.
The disclosure further provides pharmaceutical compositions for internal administration and describes treatment indications for multiple apoptosis-related disorders, including autoimmune diseases. It also describes combination/chemopotentiation approaches involving radiation and multiple chemotherapy classes and agents, including TRAIL/TRAIL agonists that activate TRAIL receptors to promote synergistic tumor cell death.
Claims Coverage
The independent claims identified are directed to two methods: treating cancer in a mammal using a compound of Formula (I) together with a second chemotherapy, and inducing apoptosis in a cancer cell by contacting the cell with the compound of Formula (I) together with a second chemotherapy. The inventive features center on the Formula (I) compound with R5 as CH2CH3 and a second chemotherapy comprising a biological agent that binds to and activates a TRAIL receptor together with one of several named agents.
Treating cancer with Formula (I) and TRAIL-receptor biological agent chemotherapy
A method of treating cancer in a mammal in need thereof by administering an effective amount of a compound of Formula (I), wherein R5 is CH2CH3 (or a pharmaceutically acceptable salt), and administering a second chemotherapy comprising a biological agent that binds to and activates a TRAIL receptor together with azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, or tioguanine.
Inducing apoptosis by contacting cancer cell with Formula (I) and TRAIL-receptor biological agent chemotherapy
A method of inducing apoptosis in a cancer cell by contacting the cancer cell with a compound of Formula (I), wherein R5 is CH2CH3 (or a pharmaceutically acceptable salt), and with a second chemotherapy comprising a biological agent that binds to and activates a TRAIL receptor together with azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, or tioguanine.
The claim set centers on combining a Formula (I) compound with R5 as CH2CH3 with a second chemotherapy defined by a TRAIL-receptor-binding and -activating biological agent, where the second chemotherapy additionally comprises one or more listed chemotherapeutic agents.
Stated Advantages
Induces apoptosis via IAP antagonism (SMAC/DIABLO vs IAPs).
Promotes synergistic tumor cell death when combined with TRAIL/TRAIL agonists that activate TRAIL receptors.
Documented Applications
Treating proliferative disorders, notably cancers.
Treating apoptosis-related conditions, including autoimmune diseases such as systemic lupus erythematosus, psoriasis, and idiopathic thrombocytopenic purpura.
Combination/chemopotentiation with radiation therapy.
Combination/chemopotentiation with multiple chemotherapy classes and agents.
Combination with TRAIL/TRAIL agonists that activate TRAIL receptors to promote synergistic tumor cell death.
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