Dual-Binding Protein for Selective MCL-1 and BCL-xL Apoptosis
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Solution Overview
Problem
Existing BH3 mimetics targeting multiple BCL-2 family proteins risk side effects due to non-specific suppression of both cancer and normal cells, necessitating a molecule that can selectively bind to multiple anti-apoptotic BCL-2 family proteins to induce apoptosis in cancer cells without affecting normal cells.
Innovation Solution
Development of a protein, such as 4H_αBM_3, which simultaneously binds to MCL-1 and BCL-xL with high affinity, enhancing apoptogenic activity and inducing apoptosis in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple BH3 mimetics are used to inhibit multiple BCL-2 family proteins, then apoptogenic activity is enhanced, but side effects increase due to non-specific suppression of normal cells
Solution Approach 1:
The patent combines multiple binding functionalities into a single bifunctional protein that can simultaneously bind to both MCL-1 and BCL-xL. This merging approach achieves the enhanced apoptogenic activity of targeting multiple BCL-2 family proteins while avoiding the side effects of using multiple separate BH3 mimetics, as the unified protein structure enables selective cancer cell targeting.
Solution Approach 2:
The invented protein serves multiple functions simultaneously: it acts as both an MCL-1 binder and a BCL-xL binder within a single molecular structure. This multi-functionality allows the protein to achieve synergistic apoptogenic effects against cancer cells that overexpress both anti-apoptotic proteins, while maintaining selectivity to avoid suppressing normal cells.
2Object-affected harmful factors
If a single BH3 mimic is used to target one BCL-2 family protein, then side effects are reduced, but apoptogenic activity is insufficient
Solution Approach 1:
The patent merges the targeting capabilities of multiple BH3 mimetics into a single bifunctional protein structure that can bind both MCL-1 and BCL-xL simultaneously. This resolves the contradiction by achieving enhanced apoptogenic activity through dual targeting while maintaining the low side effect profile of selective inhibition, as the unified protein structure enables coordinated action against both anti-apoptotic proteins.
3Reliability
If BH3 mimetics suppress BCL-2 family proteins in both cancer and normal cells, then apoptosis is induced in cancer cells, but normal cells are also affected causing side effects
Solution Approach 1:
The bifunctional protein exhibits local quality in its binding properties, with optimized affinity for cancer cell-associated MCL-1 and BCL-xL proteins. The protein structure is designed to recognize specific conformational features of these anti-apoptotic proteins in the cancer cell context, enabling selective apoptosis induction in cancer cells while sparing normal cells that do not overexpress these targets.
Data Source
AI summary
The present invention relates to a protein that simultaneously binds to both MCL-1 and BCL-xL and uses thereof. The protein of the present invention simultaneously and specifically binds to both MCL-1 and BCL-xL, which are anti-apoptotic BCL-2 family proteins whose expression is increased in various carcinomas, and thus can be usefully applied to the prevention or treatment of cancers.