Substituted indole Mcl-1 inhibitors: a patent evaluation (WO2015148854A1)
Ting Song1, Ziqian Wang1, Zhichao Zhang1
1a State Key Laboratory of Fine Chemicals, School of Chemistry , Dalian University of Technology , Dalian , China.
Abstract:
The myeloid cell leukemia 1 (Mcl-1) protein, an anti-apoptotic member of Bcl-2 family, plays a critical role in the development and maintenance of many cancers and is listed in the 'top ten' pathological factors across the diversity of human cancers. The patent described in this evaluation (WO2015148854A1) claimed substituted indole Mcl-1 inhibitors for the treatment of diseases and conditions (e.g., cancer) characterized by the over-expression or dysregulation of Mcl-1 proteins. A variety of 2-position substituents distinguished indole Mcl-1 inhibitors claimed in this patent from another two patents by AbbVie Inc. (WO2008131000A2 and WO2008130970A1). They exhibited low-nanomolar binding affinities and >100-fold selectivity over Bcl-2 and Bcl-xL in vitro, and low-micromolar killing abilities against a panel of tumour cell lines. Moreover, the compounds in this patent revealed that the structural basis for selective Mcl-1 inhibitors may not completely depend on the 5 known binding hot-spots, and conformational flexibility of Mcl-1 protein could contribute to the binding specificity.
Insights
New indole Mcl-1 inhibitors show promise for cancer treatment. These compounds exhibit high binding affinity and selectivity, offering a potential new therapeutic strategy for cancers driven by Mcl-1 protein dysregulation.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Myeloid cell leukemia 1 (Mcl-1) is an anti-apoptotic protein crucial for cancer cell survival and is a significant pathological factor in numerous human cancers.
- Overexpression or dysregulation of Mcl-1 contributes to cancer development and maintenance, making it a key therapeutic target.
Purpose of the Study:
- To evaluate a patent (WO2015148854A1) detailing novel substituted indole Mcl-1 inhibitors for treating Mcl-1-related diseases, including cancer.
- To compare these novel inhibitors with existing Mcl-1 inhibitors from AbbVie Inc. patents (WO2008131000A2 and WO2008130970A1).
Main Methods:
- Analysis of patent claims focusing on substituted indole Mcl-1 inhibitors, particularly variations in 2-position substituents.
- In vitro assessment of binding affinities and selectivity against Bcl-2 and Bcl-xL.
- Evaluation of cytotoxic effects against various tumor cell lines.
Main Results:
- The novel indole Mcl-1 inhibitors demonstrated low-nanomolar binding affinities and over 100-fold selectivity for Mcl-1 compared to Bcl-2 and Bcl-xL.
- These compounds displayed low-micromolar killing abilities against a panel of cancer cell lines.
- The findings suggest that Mcl-1 inhibitors' selectivity may not solely rely on the known 5 binding hot-spots, highlighting the role of protein conformational flexibility.
Conclusions:
- The substituted indole Mcl-1 inhibitors described in WO2015148854A1 represent a promising class of compounds for cancer therapy.
- These inhibitors offer improved binding affinity and selectivity, potentially overcoming resistance mechanisms associated with other Bcl-2 family inhibitors.
- The study underscores the importance of Mcl-1 protein's structural flexibility in designing potent and selective inhibitors.
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