SMAC Mimetics Antagonize IAPs to Restore Apoptosis
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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 that target and inhibit IAPs, including SMAC mimetics, to antagonize IAP activities, thereby increasing apoptosis in abnormally proliferating cells, which are administered alone or in combination with other therapeutic agents.
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 uses SMAC mimetics as intermediary molecules that bind to IAPs and disrupt their inhibitory function. These small molecule compounds act as mediators between the therapeutic goal (inducing apoptosis) and the target (IAP proteins), allowing chemotherapy to overcome IAP-mediated resistance without directly modifying the IAP structure
Solution Approach 2:
The patent modifies the natural SMAC peptide structure by changing its chemical parameters to create stable, cell-permeable mimetics. These parameter changes include incorporating non-natural amino acids, modifying peptide bonds, and optimizing molecular properties to enhance binding affinity and stability while maintaining the ability to inhibit IAPs
2Productivity
If SMAC mimetics are administered to antagonize IAP activities, then apoptosis is increased in abnormally proliferating cells, but the compounds must overcome the stability and resistance mechanisms of IAPs
Solution Approach 1:
The patent creates composite molecular structures by combining multiple functional elements within the SMAC mimetic: cell penetration peptides, IAP-binding domains with optimized affinity, and stabilizing structural motifs. This composite approach allows a single compound to simultaneously overcome multiple barriers including cell membrane permeability, IAP binding affinity, and metabolic stability
Solution Approach 2:
The patent performs preliminary optimization of the SMAC mimetic structure before administration, including pre-screening for stability against proteases, optimizing cell permeability properties, and pre-validating binding affinity to multiple IAP family members. This preliminary action ensures the compound is pre-equipped to withstand the challenging intracellular environment and effectively inhibit IAPs upon delivery
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.