IAP Antagonist Compounds Modulating BIR3 Domain to Overcome Chemotherapy Resistance
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for proliferative disorders such as cancer are hindered by the overexpression of Inhibitors of Apoptosis Proteins (IAPs), which prevent apoptosis and confer resistance to chemotherapy, necessitating the development of compounds that can modulate IAP activity to promote cell death.
Innovation Solution
Development of specific compounds, including those represented by Formula (I), which modulate IAP activity by inhibiting BIR3 and BIR2-3 domains, thereby enhancing apoptosis in abnormal cells, and their use in pharmaceutical compositions for treating various medical conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If IAPs are overexpressed in tumor cells, then cell survival is enhanced and resistance to chemotherapy is conferred, but apoptosis is prevented and abnormal proliferation continues
Solution Approach 1:
The patent introduces SMAC mimetics as intermediary molecules that bind to IAPs and disrupt their inhibitory function. These mimetics contain the AVPI motif that specifically interacts with BIR domains of IAPs, acting as a mediator between the therapeutic goal (inducing apoptosis) and the target (IAPs). This allows the transfer of pro-apoptotic signal from external stimuli to the caspase activation pathway by blocking IAP-mediated inhibition.
Solution Approach 2:
The patent modifies the natural SMAC peptide structure by incorporating non-natural amino acids and modifying the AVPI motif to create stable oral bioavailable compounds. These parameter changes include introducing deuterated amino acids, cyclic constraints, and bioisosteric replacements to enhance metabolic stability, cellular permeability, and binding affinity while maintaining the ability to inhibit IAPs and induce apoptosis in resistant tumor cells.
2Productivity
If conventional chemotherapy is used, then tumor cell proliferation is targeted, but IAP overexpression confers resistance and treatment efficacy is reduced
Solution Approach 1:
The patent employs SMAC mimetics to preliminarily inhibit IAPs before chemotherapy treatment or in combination therewith. By pre-blocking the protective IAP-caspase interaction, the system sensitizes tumor cells to apoptotic stimuli, making them more vulnerable to subsequent chemotherapy-induced cell death. This preliminary action removes the resistance barrier that IAP overexpression creates, thereby enhancing overall treatment efficacy.
Solution Approach 2:
The patent develops composite therapeutic regimens that combine SMAC mimetics with conventional chemotherapy agents. The SMAC mimetic component (containing modified AVPI motif) works synergistically with chemotherapy drugs to overcome IAP-mediated resistance. This composite approach integrates two different mechanisms of action: direct IAP inhibition by the mimetic and DNA/cell cycle targeting by chemotherapy, resulting in enhanced anti-tumor efficacy compared to either agent alone.
3Object-generated harmful factors
If SMAC mimetics are developed to inhibit IAPs, then apoptosis is promoted in tumor cells, but compound stability and oral bioavailability must be maintained
Solution Approach 1:
The patent systematically modifies the SMAC peptide parameters to achieve optimal balance between IAP-inhibiting activity, metabolic stability, and oral bioavailability. Specific modifications include: (1) incorporating deuterated amino acids to slow metabolic degradation, (2) introducing cyclic constraints to enhance conformational stability and binding affinity, (3) using bioisosteric replacements to improve cellular permeability, and (4) optimizing the AVPI motif sequence for maximum IAP binding while maintaining protease resistance. These parameter changes collectively enable the compounds to remain stable in vivo while effectively inducing apoptosis.
Data Source
AI summary
There are disclosed compounds that modulate the activity of inhibitors of apoptosis (IAPs), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders and disorders of dysregulated apoptosis, such as cancer, utilizing the compounds of the invention.