Allosteric CBFβ Inhibitors for RUNX-Dependent Cancer
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Solution Overview
Problem
Current small molecule inhibitors are ineffective in targeting protein-protein interactions, particularly for transcription factors like RUNX proteins and CBFβ, which are critical in various cancers, due to the long-held belief that such interactions are 'undruggable', limiting therapeutic options for cancers that do not involve the CBFβ-SMMHC fusion protein.
Innovation Solution
Development of compounds that bind to wild-type CBFβ, inhibiting its interaction with RUNX proteins using an allosteric mechanism, thereby displacing CBFβ from RUNX1 in cells and altering gene expression, which are effective at low micromolar concentrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If small molecule inhibitors are used to target protein-protein interactions in transcription factors, then therapeutic options for cancer treatment are expanded, but the effectiveness is limited due to the long-held belief that such interactions are 'undruggable'
Solution Approach 1:
The patent employs an allosteric mechanism where small molecule inhibitors bind to a distant site on the CBFβ protein (not the RUNX binding interface), inducing conformational changes that propagate to the protein-protein interaction interface. This intermediary binding approach allows small molecules to indirectly modulate the CBFβ-RUNX interaction, overcoming the traditional belief that such interfaces are undruggable.
Solution Approach 2:
The invention changes the binding parameters by targeting an allosteric site rather than the orthosteric RUNX binding site. This parameter change in binding location enables small molecules to effectively modulate the protein-protein interaction, achieving reliable therapeutic effects where previous approaches failed.
2Reliability
If inhibitors target the CBFβ-SMMHC fusion protein, then inv(16) leukemia is treated effectively, but no therapeutic benefit is achieved for other cancers expressing wild-type CBFβ
Solution Approach 1:
The patent develops inhibitors that bind to wild-type CBFβ with high affinity, making them universally applicable to multiple cancer types including AML, MDS, and solid tumors that express wild-type CBFβ. This universal mechanism extends therapeutic benefit beyond the specific inv(16) leukemia case to a broader range of RUNX-signaling-dependent cancers.
Solution Approach 2:
Instead of targeting the abnormal CBFβ-SMMHC fusion protein as previously done, the invention inverts the approach by targeting the wild-type CBFβ protein itself. This inversion reveals that the wild-type protein is the actual therapeutic target for a broader spectrum of cancers, expanding adaptability while maintaining effectiveness.
3Reliability
If small molecules are designed to bind CBFβ and inhibit RUNX interaction, then cancer cell proliferation is inhibited and apoptosis is induced, but the design complexity increases due to the need for allosteric binding site identification
Solution Approach 1:
The patent extracts and focuses on the allosteric binding site as a separate target from the RUNX interaction interface. By isolating this distal binding site as the primary target, the design process becomes more manageable despite the added complexity of allosteric mechanism understanding, as researchers can focus on one specific binding pocket rather than the entire protein interface.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These compounds demonstrate clear biological effects consistent with on-target RUNX protein activity, showing potential in treating RUNX-signaling-dependent cancers expressing wild-type CBFβ by inhibiting cancer cell proliferation and inducing apoptosis, thus offering a new therapeutic approach for cancers beyond those involving the CBFβ-SMMHC fusion protein.
Implementation Method 1
inhibiting its interaction with RUNX proteins using an allosteric mechanism
Data Source
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Figure 2B~3A
AI summary
This invention relates to compounds that bind to wild-type CBFβ and inhibit CBFβ binding to RUNX proteins. The potent compounds of the invention inhibit this protein-protein interaction at low micromolar concentrations, using allosteric mechanism to achieve inhibition, displace wild-type CBFβ from RUNX1 in cells, change occupancy of RUNX1 on target genes, and alter gene expression of RUNX1 target genes. These inhibitors show clear biological effects consistent with on-target RUNX protein activity. Pharmaceutical compositions containing a compound of the invention and a pharmaceutically acceptable carrier represent a separate embodiment of the invention. Another embodiment of the invention are methods of treating a RUNX-signaling-dependent cancer that expresses wild-type CBFβ in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the invention. In one embodiment, the cancer is selected from the group consisting of a RUNX-signaling-dependent leukemia that expresses wild-type CBFβ, lung cancer, bladder cancer, ovarian cancer, uterine cancer, endometrial cancer, breast cancer, liver cancer, pancreatic cancer, stomach cancer, cervical cancer, lymphoma, leukemia, acute myeloid leukemia, acute lymphocytic leukemia, salivary gland cancer, bone cancer, brain cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, skin cancer, melanoma, squamous cell carcinoma of the tongue, pleomorphic adenoma, hepatocellular carcinoma, pancreatic cancer, squamous cell carcinoma, and/or adenocarcinoma. In another embodiment, the compounds of the invention can be used to treat a leukemia, lung cancer, ovarian cancer, and/or breast cancer.