A series of alkyl coumarin-tethered phenyl quinazolinones were rationally designed and synthesized as hypoxia-targeted dual hCA IX/HSP90α inhibitors, exhibiting potent, highly selective inhibition of hCA IX (in the nanomolar range), while displaying negligible activity against the off-target isoforms hCA I and II.
Amal S. Elgohary, Mervat H. El-Hamamsy, N. Sharafeldin et al.· RSC Advances· 0 citations
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
The current study devised and synthesized a novel class of pyrazole derivatives based on indole as possible inhibitors of cyclin‐dependent kinase‐2 (CDK‐2). 1H NMR, 13C NMR, NOESY, HMQC, and elemental analysis were used to confirm the structural integrity of the synthesized compounds. Promising CDK‐2 inhibitory activity was observed in biological assays, and numerous compounds exhibited sub‐micromolar IC50 values. Compound 5 d outperformed the reference inhibitor Roscovitine (IC50 = 0.716 µM) as the most potent inhibitor (IC50 = 0.536 µM), followed by compound 9 g (IC50 = 0.675 µM). SAR analysis showed that the observed activity was significantly influenced by the electronic nature of the added substituents as well as the orientation of the indole bond, with brominated derivatives exhibiting greater potency. The antiproliferative activity of the most potent compounds against the cancer cell lines HepG2, HCT‐116, and MCF‐7 was further assessed. In addition to having an enhanced selectivity index for normal MCF‐10A cells (SI = 8.00 vs. 4.96 for Roscovitine), compound 5 d had the greatest activity against MCF‐7 cells (IC50 = 6.78 µM), surpassing Roscovitine (IC50 = 8.11 µM). According to mechanistic investigations, compound 5 d significantly reduced the S‐phase population, markedly promoted apoptosis, and caused G1 and G2/M cell‐cycle arrest. Additionally, the consistent binding of compound 5 d within the ATP‐binding pocket of CDK‐2 was confirmed by molecular docking and molecular dynamics simulations, and attractive drug‐like and pharmacokinetic features, similar to those of Roscovitine, were demonstrated by in silico ADMET predictions. All of these results point to compound 5 d as a promising lead scaffold for developing potent CDK‐2‐targeted anticancer agents.
Wagdy M. Eldehna, Zainab M. Elsayed, Mohamed R. Elnagar et al.· Drug development research (P...· 0 citations
