Runx3 modified protein for prevention or treatment of cancer
Inventors
Bae, Suk Chul • Lee, Jung Won • Lee, You Soub
Assignees
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Publication Number
US-11931401-B2
Publication Date
2024-03-19
Expiration Date
Abstract
In the present invention, it was confirmed that the modified protein in which the 356th serine of Runx3 is substituted with alanine has an increased activity of maintaining the complex with Brd2 by more than 10 times compared to the wild-type Runx3, and the apoptosis effect is improved in various cancer cell lines compared to the wild-type Runx3. Therefore, the modified protein in which the 356th serine of Runx3 is substituted with an amino acid that cannot be phosphorylated by a kinase of the present invention, the polynucleotide coding thereof, the vector carrying the polynucleotide, or the virus or cell transformed with the vector can be used as a therapeutic agent for various cancers.
Core Innovation
The invention relates to treating cancer by administering a modified protein, a polynucleotide encoding the modified protein, a vector carrying the polynucleotide, or a virus or cell transformed with the vector. The modified protein is a Runx3 (Runt-related transcription factor 3) protein in which the 356th serine according to SEQ ID NO: 2 is substituted with an amino acid that cannot be phosphorylated by a kinase.
The modified Runx3 protein is described in the context of a Runx3-BRD2 complex, where maintaining the BRD2-RUNX3 complex is connected to cancer cell killing and apoptosis. The Ser-356 substitution is reported to increase maintenance of the BRD2-RUNX3 complex more than 10× compared to wild-type, and improved apoptosis/cell-killing efficacy is reported for the modified Runx3 variant.
The cancer indication is limited to lung, stomach, or pancreatic cancer, including solid cancer. The described compositions further include polynucleotides, vectors, and virus or cell delivery options, including adenovirus, retrovirus, lentivirus, herpes simplex virus, and AAV, along with corresponding sequence-related references such as SEQ ID NO:2 and SEQ ID NO:4.
Claims Coverage
The document provides one independent claim that covers a method of treating cancer by administering a modified Runx3 protein, or the genetic and delivery systems for expressing or providing that modified protein, with the cancer limited to lung, stomach, or pancreatic cancer. The claim set includes five dependent inventive features that refine the non-phosphorylatable substitution, sequence encoding relationships, vector form, an in vitro binding performance threshold, and a narrower indication for lung cancer.
Non-phosphorylatable Ser-356 Runx3 for cancer treatment
A method for treating lung, stomach, or pancreatic cancer by administering a modified Runx3 protein in which the 356th serine according to SEQ ID NO: 2 is substituted with an amino acid that cannot be phosphorylated by a kinase, or administering corresponding polynucleotide, vector, virus, or cell providing the modified protein in a pharmaceutically effective amount.
Non-phosphorylatable substitution amino acid selection
The method of treating cancer includes using an amino acid that cannot be phosphorylated by a kinase selected from alanine, isoleucine, leucine, or valine as the substitution for the 356th serine.
Polynucleotide encoding relationship using SEQ ID references
The method specifies that SEQ ID NO:2 is encoded by a polynucleotide represented by SEQ ID NO:4.
Vector form as linear DNA or plasmid DNA
The method specifies that the vector carrying the polynucleotide is linear DNA or plasmid DNA.
In vitro BRD2 binding maintenance threshold versus wild-type
A cancer treatment method in which the modified protein binds BRD2 in vitro at least 10 times longer than wild-type Runx3.
Lung cancer indication
The method for treating cancer is applied specifically to lung cancer.
Overall claim coverage centers on cancer treatment using a Runx3 protein with the 356th serine substituted by an amino acid that cannot be phosphorylated by a kinase, with additional refinements specifying allowable substitution identities, SEQ ID encoding relationships, vector form, and a quantitative in vitro BRD2 binding maintenance threshold versus wild-type, while narrowing the indication to lung cancer in a dependent refinement.
Stated Advantages
Increased maintenance of the BRD2-RUNX3 complex more than 10× compared to wild-type.
Improved apoptosis/cell-killing efficacy.
Documented Applications
Treating cancer in a subject with the cancer limited to lung, stomach, or pancreatic cancer (solid cancer).
The method is specifically documented for lung cancer.
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