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

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 (K _i = 0.6 μM) without apparent binding to Bcl-2 or BCL-X_L. 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.