ArticleChemMedChem2016
Structural Re-engineering of the α-Helix Mimetic JY-1-106 into Small Molecules: Disruption of the Mcl-1-Bak-BH3 Protein-Protein Interaction with 2,6-Di-Substituted Nicotinates.
Article in ChemMedChem, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 28 citations in OpenAlex.
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- The polypharmacy combination of the BCL-2 inhibitor venetoclax (VEN) and the FLT3 inhibitor gilteritinib (GIL) is more active in acute myeloid leukemia cells than novel polypharmacologic BCL-2/FLT3 VEN-GIL hybrid single-molecule inhibitors.European journal of medicinal chemistry · 2025Article
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- Scaffold hopping from indoles to indazoles yields dual MCL-1/BCL-2 inhibitors from MCL-1 selective leads.RSC medicinal chemistry · 2022Article
- Recent applications of covalent chemistries in protein-protein interaction inhibitors.RSC medicinal chemistry · 2022Review
- SThe Journal of organic chemistry · 2021Article
- Discovery ofJournal of nuclear medicine : official publication, Society of Nuclear Medicine · 2019Article
- Inhibitors of protein-protein interactions (PPIs): an analysis of scaffold choices and buried surface area.Current opinion in chemical biology · 2018Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
The disruption of aberrant protein-protein interactions (PPIs) with synthetic agents remains a challenging goal in contemporary medicinal chemistry but some progress has been made. One such dysregulated PPI is that between the anti-apoptotic Bcl-2 proteins, including myeloid cell leukemia-1 (Mcl-1), and the α-helical Bcl-2 homology-3 (BH3) domains of its pro-apoptotic counterparts, such as Bak. Herein, we describe the discovery of small-molecule inhibitors of the Mcl-1 oncoprotein based on a novel chemotype. Particularly, re-engineering of our α-helix mimetic JY-1-106 into 2,6-di-substituted nicotinates afforded inhibitors of comparable potencies but with significantly decreased molecular weights. The most potent inhibitor 2-(benzyloxy)-6-(4-chloro-3,5-dimethylphenoxy)nicotinic acid (1 r: Ki =2.90 μm) likely binds in the p2 pocket of Mcl-1 and engages R263 in a salt bridge through its carboxylic acid, as supported by 2D (1) H-(15) N HSQC NMR data. Significantly, inhibitors were easily accessed in just four steps, which will facilitate future optimization efforts.
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