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
Poly(ADP‐ribose) polymerase‐1 (PARP‐1) plays a central role in the repair of DNA single‐strand breaks and represents an established therapeutic target in cancer treatment. In this study, a series of novel oxadiazole–morpholine hybrid compounds was designed and synthesized using a structure‐based drug design approach to target the catalytic domain of PARP‐1. The synthesized compounds were evaluated for their cytotoxic activity against breast and ovarian cancer cells, PARP‐1 inhibitory potency, and apoptosis‐inducing effects. Among the tested compounds, 12a exhibited potent cytotoxic activity against MDA‐MB‐231 cells (IC50 = 1.23 μM), surpassing the reference drug olaparib (IC50 = 3.45 μM). Compound 12a also demonstrated strong PARP‐1 inhibitory activity (IC50 = 0.034 μM), comparable to olaparib (IC50 = 0.012 μM). Flow cytometric analyses revealed that compound 12a significantly induced apoptotic cell death and altered cell cycle progression. Molecular docking studies suggested plausible binding interactions within the PARP‐1 catalytic site, supporting the observed biological activity. These findings identify oxadiazole–morpholine hybrids as promising scaffolds for further optimization as PARP‐1 inhibitors.
Nader R Albujuq, Khaled M. Darwish, S. Fahmy et al.· Drug development research (P...· 0 citations
Compound 4v emerged as a leading candidate, showing EGFR kinase inhibitory activity comparable to Erlotinib, and computational analysis of 4v and EGFR molecular binding suggests that it serves as a superior binder to the inactive EGFR conformation.
Amr Elagamy, Mohamed S. Nafie, Ahmed Elnahrawy et al.· European journal of medicina...· 0 citations
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