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Scaffold hopping from indoles to indazoles yields dual MCL-1/BCL-2 inhibitors from MCL-1 selective leads
Brandon Drennen1, Christopher C Goodis1, Nathan Bowen2
1University of Maryland School of Pharmacy, Department of Pharmaceutical Sciences 20 N. Pine St. Baltimore MD 21201 USA steven.fletcher@rx.umaryland.edu.
Abstract:
Overexpression of the anti-apoptotic BCL-2 proteins is associated with the development and progression of a range of cancers. Venetoclax, an FDA-approved BCL-2 inhibitor, is fast becoming the standard-of-care for acute myeloid leukemia and chronic lymphocytic leukemia. However, the median survival offered by venetoclax is only 18 months (as part of a combination therapy regimen), and one of the primary culprits for this is the concomitant upregulation of sister anti-apoptotic proteins, in particular MCL-1 (and BCL-xL), which provides an escape route that manifests as venetoclax resistance. Since inhibition of BCL-xL leads to thrombocytopenia, we believe that a dual MCL-1/BCL-2 inhibitor may provide an enhanced therapeutic effect relative to a selective BCL-2 inhibitor. Beginning with a carboxylic acid-containing literature compound that is a potent inhibitor of MCL-1 and a moderate inhibitor of BCL-2, we herein describe our efforts to develop dual inhibitors of MCL-1 and BCL-2 by scaffold hopping from an indole core to an indazole framework. Subsequently, further elaboration of our novel N2-substituted, indazole-3-carboxylic acid lead into a family of indazole-3-acylsulfonamides resulted in improved inhibition of both MCL-1 and BCL-2, possibly through occupation of the p4 pocket, with minimal or no inhibition of BCL-xL.
Insights
Developing novel dual MCL-1/BCL-2 inhibitors offers a promising strategy to overcome venetoclax resistance in cancer therapy. These new compounds show enhanced inhibition of target proteins without affecting BCL-xL, potentially improving patient outcomes.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Overexpression of anti-apoptotic BCL-2 proteins drives cancer development and progression.
- Venetoclax, a BCL-2 inhibitor, is a standard treatment for certain leukemias but faces resistance due to MCL-1 and BCL-xL upregulation.
- Inhibiting BCL-xL causes thrombocytopenia, necessitating alternative therapeutic strategies.
Purpose of the Study:
- To develop novel dual inhibitors targeting both MCL-1 and BCL-2 to overcome venetoclax resistance.
- To explore scaffold hopping from indole to indazole frameworks for improved drug design.
- To create compounds with minimal BCL-xL inhibition to avoid thrombocytopenia.
Main Methods:
- Scaffold hopping from an indole core to an indazole framework.
- Chemical modification of a lead compound to create indazole-3-acylsulfonamides.
- Assaying inhibition of MCL-1, BCL-2, and BCL-xL proteins.
Main Results:
- Successful development of novel N2-substituted, indazole-3-carboxylic acid derivatives.
- Achieved dual inhibition of MCL-1 and BCL-2 with improved potency.
- Minimized inhibition of BCL-xL, suggesting a potentially safer therapeutic profile.
Conclusions:
- Dual MCL-1/BCL-2 inhibition is a viable strategy to overcome venetoclax resistance.
- Indazole-3-acylsulfonamides represent a promising new class of anti-cancer agents.
- These novel compounds may offer enhanced efficacy and reduced toxicity compared to existing therapies.
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