Add time:07/14/2019 Source:sciencedirect.com
The B-cell lymphoma-2 (Bcl-2) family proteins are attractive targets for cancer therapy. In our previous work, the structure-activity relationship of WL-276 was studied. According to the results, rhodanine derivatives show potent binding affinity for Bcl-2 and Mcl-1 protein and show weaker activity against Bcl-XL protein. Based on the previous results, a new class of indole-3-carboxylic acid-based derivatives were designed and synthesized as Bcl-2/Mcl-1 dual inhibitors. Among them, compound 17 has a Ki value of 0.26 μM for Bcl-2 protein and is better than WL-276. Furthermore, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a Ki value of 72 nM. Especially, compound 31 can selectively acting on Bcl-2 and Mcl-1 protein but not Bcl-XL protein, which has great significance for developing dual inhibitors targeting Bcl-2 and Mcl-1 protein, as well as specific antitumor abilities in cells.
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