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ACS Omega

ACS Omega

IF: 3.7
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Discovery of Phenylpyrazole Derivatives as a New Class of Selective Inhibitors of MCL-1 with Antitumor Activity

Published:13 June 2024 DOI: 10.1021/acsomega.4c02021
Qineng Gong, Chunpu Li, Haojie Wang, Jinrui Cao, Zuo Li, Mi Zhou, Yan Li, Yong Chu*, Hong Liu* and Renxiao Wang*, 

Abstract

MCL-1, an antiapoptotic member of the BCL-2 family, is dysregulated and overexpressed in various tumors. In tumors with MCL-1 overexpression, selective inhibitors of MCL-1 are expected to overcome the drug resistance caused by BCL-2 inhibitors currently used in clinical treatment. Here, we employed docking-based virtual screening to identify an active hit, LC126, with binding affinity around 10 μM for MCL-1 and BCL-2. Under the guidance of structure-based design, we obtained a few selective inhibitors of MCL-1 after three rounds of structural optimization. The representative compound GQN-B37-E exhibited binding affinity for MCL-1 at the submicromolar range (Ki = 0.6 μM) without apparent binding to BCL-2 or BCL-XL. 15N-heteronuclear single-quantum coherence NMR spectra suggested that this compound binds to the BH3-domain-binding pocket in the MCL-1 surface. Cellular assays revealed that GQN-B37-Me, the precursor of GQN-B37-E, is effective particularly on leukemia cells (such as H929 and MV-4–11) to induce caspase-dependent apoptosis. Its interaction with MCL-1 in cells was confirmed by coimmunoprecipitation. Administration of GQN-B37-Me to MV-4–11 xenograft mice at 50 mg/kg every 2 days for 20 days led to 43% tumor growth inhibition. GQN-B37-Me also exhibited reasonable in vitro stability in GSH and liver microsomes from several species. This new class of MCL-1 inhibitor may have potential to be further developed into a preclinical candidate for treating leukemia.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
A-1210477 1668553-26-1 C46H55N7O7S 105 suppliers $17.00-$3791.00
A-1210477 1668553-26-1 C46H55N7O7S 105 suppliers $17.00-$3791.00
A-1210477 1668553-26-1 C46H55N7O7S 105 suppliers $17.00-$3791.00
A-1210477 1668553-26-1 C46H55N7O7S 105 suppliers $17.00-$3791.00

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