Isocitrate dehydrogenase (IDH) enzymes convert isocitrate to α-ketoglutarate. When IDH1 or IDH2 is mutated, the enzyme gains a new function, and the oncometabolite D-2-hydroxyglutarate (D-2-HG) accumulates. Its epigenetic and metabolic effects depend on the tumor context. This review classifies mutant IDH inhibitors by chemical scaffold and relates their binding in the allosteric pocket to structure-activity trends, isoform selectivity, brain penetration, and clinical outcome. Mutant IDH1, mutant IDH2, pan-IDH, and covalent inhibitors are compared, with lessons from successful and failed clinical candidates. Resistance is treated separately: secondary mutations, isoform switching, metabolic adaptation, rational combinations, PROTAC degraders, and biomarkers. Since reduced 2-HG indicates target engagement rather than clinical benefit, design priorities for the next generation of IDH-directed agents are outlined.
Moataz A. Shaldam, Anwar A. El-Hamaky, Nourhan A. Khattab et al.· Drug Discovery Today· 0 citations
Background: Among natural products, vanillin (Van), a major component of Vanilla planifolia, exhibits multiple bioactivities, including antimicrobial effects. Methods: In this study, Van, its analogues o-vanillin (oVan), iso-vanillin (iVan), ethylvanillin (eVan), and a library of newly synthesized derivatives were evaluated against Helicobacter pylori strains with distinct antibiotic susceptibilities. Time-kill kinetics, antibacterial spectrum, and viability in a normal gastric cell line GES-1, were also assessed. Results: Van showed minimal or no activity (MIC and MBC > 128 µg/mL), whereas structural modifications markedly improved anti-H. pylori activity, with MIC values as low as 4 µg/mL. Compounds 16V, 20oV, and 29eV were among the most potent (MIC90 = 4–16 µg/mL). Activity depended on both the vanilloid core and substituent type. The compounds were inactive against representative Gram-negative and Gram-positive bacteria (MIC > 128 µg/mL). Selected compounds preserved viability in GES-1 cells. Hierarchical clustering, artificial neural clustering, and principal component analysis identified potency-related architectural motifs and strain-specific activity. Docking against H. pylori urease suggested that several compounds, particularly 16V, may interact with the enzyme, providing preliminary support for a possible involvement of this target. Conclusions: Systematic modification of the vanilloid scaffold generated selective and relatively non-cytotoxic anti-H. pylori hit compounds and confirmed the value of natural metabolites in antibacterial drug discovery.
Ilaria D’Agostino, Strahinja Z. Kovačević, Moataz A. Shaldam et al.· Antibiotics· 0 citations
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