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Published on: May 15, 2019
Evaluation and critical assessment of putative MCL-1 inhibitors
S Varadarajan1, M Vogler, M Butterworth
1MRC Toxicology Unit, University of Leicester, Leicester, UK.
Abstract:
High levels of BCL-2 family proteins are implicated in a failed/ineffective apoptotic programme, often resulting in diseases, including cancer. Owing to their potential as drug targets in cancer therapy, several inhibitors of BCL-2 family proteins have been developed. These primarily target specific members of the BCL-2 family, particularly BCL-2 and BCL-XL but are ineffective against MCL-1. Major efforts have been invested in developing inhibitors of MCL-1, which is commonly amplified in human tumours and associated with tumour relapse and chemoresistance. In this report, the specificity of several BCL-2 family inhibitors (ABT-263, UCB-1350883, apogossypol and BH3I-1) was investigated and compared with putative MCL-1 inhibitors designed to exhibit improved or selective binding affinities for MCL-1 (TW-37, BI97C1, BI97C10, BI112D1, compounds 6 and 7, and MCL-1 inhibitor molecule (MIM-1)). ABT-263, BI97C1, BI112D1, MIM-1 and TW-37 exhibited specificity in inducing apoptosis in a Bax/Bak- and caspase-9-dependent manner, whereas the other agents showed no killing activity, or little or no specificity. Of these inhibitors, only ABT-263 and UCB-1350883 induced apoptosis in a BCL-2- or BCL-XL-dependent system. In cells that depend on MCL-1 for survival, ABT-263 and TW-37 induced extensive apoptosis, suggesting that at high concentrations these inhibitors have the propensity to inhibit MCL-1 in a cellular context. TW-37 induced apoptosis, assessed by chromatin condensation, caspase processing and phosphatidylserine externalisation, in a BAK-dependent manner and in cells that require MCL-1 for survival. TW-37-mediated apoptosis was also partly dependent on NOXA, suggesting that derivatives of TW-37, if engineered to exhibit better selectivity and efficacy at low nanomolar concentrations, may provide useful lead compounds for further synthetic programmes. Expanded medicinal chemistry iteration, as performed for the ABT series, may likewise improve the potency and specificity of the evaluated MCL-1 inhibitors.
Insights
Several BCL-2 family protein inhibitors were tested for cancer therapy. TW-37 showed promise in inducing apoptosis by targeting MCL-1, suggesting it as a lead compound for future drug development.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- High BCL-2 family protein levels are linked to cancer and chemoresistance.
- Current inhibitors target BCL-2 and BCL-XL but are ineffective against MCL-1.
- MCL-1 is a key target due to its amplification in tumors and association with relapse.
Purpose of the Study:
- To investigate and compare the specificity of various BCL-2 family inhibitors.
- To evaluate the efficacy of MCL-1 inhibitors, including TW-37, BI97C1, and MIM-1.
- To identify potential lead compounds for novel cancer therapeutics targeting MCL-1.
Main Methods:
- Assessed apoptosis induction by BCL-2 family inhibitors.
- Compared inhibitor specificity against BCL-2, BCL-XL, and MCL-1.
- Utilized assays for chromatin condensation, caspase processing, and phosphatidylserine externalization.
Main Results:
- ABT-263, BI97C1, BI112D1, MIM-1, and TW-37 induced apoptosis in a Bax/Bak- and caspase-9-dependent manner.
- TW-37 demonstrated BAK-dependent apoptosis in MCL-1-dependent cells, partly via NOXA.
- ABT-263 and TW-37 showed apoptosis induction in MCL-1-dependent cells, indicating potential MCL-1 inhibition.
Conclusions:
- TW-37 shows potential as a lead compound for developing selective MCL-1 inhibitors.
- Further medicinal chemistry efforts can enhance the potency and specificity of MCL-1 inhibitors.
- Targeting MCL-1 remains a critical strategy for overcoming cancer chemoresistance.
