Macrocyclic Indole Derivatives Inhibit MCL-1 to Overcome Cancer Resistance
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Solution Overview
Problem
Current therapies face resistance due to deregulated apoptotic signaling in cancer cells, particularly because MCL-1 is highly expressed in various cancers, leading to increased cancer cell survival and resistance to treatments like chemotherapeutics and radiation.
Innovation Solution
Development of macrocyclic indole derivatives that inhibit the anti-apoptotic activity of MCL-1 by disrupting its interaction with pro-apoptotic proteins, thereby inducing apoptosis in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If MCL-1 is highly expressed in cancer cells, then cancer cell survival is increased and resistance to chemotherapeutics and radiation is enhanced, but the ability to induce apoptosis is reduced
Solution Approach 1:
The patent extracts and inhibits the specific anti-apoptotic function of MCL-1 by designing compounds that selectively bind to MCL-1's BH3 domain, preventing its interaction with pro-apoptotic proteins like BAX and BAK, thereby removing the protective effect without affecting other cellular functions
Solution Approach 2:
The patent changes the binding parameters between MCL-1 and pro-apoptotic proteins by introducing small molecule inhibitors that alter the affinity and interaction dynamics, shifting the balance from pro-survival to pro-apoptotic state in cancer cells
2Productivity
If conventional chemotherapeutics and radiation are used to induce apoptosis, then cancer cell death is achieved, but resistance develops due to upregulated MCL-1 expression
Solution Approach 1:
The patent introduces MCL-1 inhibitors as intermediary molecules that mediate between the therapeutic goal (inducing apoptosis) and the resistance mechanism (MCL-1 upregulation), directly blocking the resistance pathway to restore sensitivity to apoptosis-inducing therapies
Solution Approach 2:
The patent applies preliminary inhibition of MCL-1 before or combined with conventional chemotherapy or radiation, preemptively blocking the resistance mechanism before it can develop or counteract the treatment effect
Data Source
AI summary
The present invention relates to macrocyclic indole derivatives of general formula (I)in which R1, R2, R3, R4, R5, R6, A and L are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.