This article and associated images are based on a poster originally authored by Rania Hamdy, Ahmed M. Almehdi, Samar Damiati, Ihsan A. Shehadi, Sameh S. M. Soliman and Andrew D. Westwell and presented at ELRIG Drug Discovery 2026 in affiliation with University of Sharjah.
This poster is being hosted on this website in its raw form, without modifications. It has not undergone peer review but has been reviewed to meet AZoNetwork's editorial quality standards. The information contained is for informational purposes only and should not be considered validated by independent peer assessment.
Abstract
Image Credit: Rania Hamdy et al., in partnership with ELRIG (UK) Ltd.
Bcl-2 is a key anti-apoptotic protein that promotes cancer cell survival, making it an attractive therapeutic target. This study developed novel Bcl-2 inhibitors, identifying R4, R14, R17, and R23 as promising anticancer compounds (IC50 = 1.46– 7.67 μM). ELISA binding assays confirmed potent Bcl-2 inhibition by R4, R14, and R23 (IC50 = 0.25–0.63 μM). Notably, R23 induced apoptosis and G1-phase cell cycle arrest, while computational analyses supported its stable binding to Bcl-2, highlighting its therapeutic potential.
Rational design
Image Credit: Rania Hamdy et al., in partnership with ELRIG (UK) Ltd.
Methods
Image Credit: Rania Hamdy et al., in partnership with ELRIG (UK) Ltd.
Safety against HDF
Image Credit: Rania Hamdy et al., in partnership with ELRIG (UK) Ltd.
Compound R23 exhibited the highest predicted selectivity for Bcl-2 over Bcl-xL (ΔG = −12.2 kcal/mol) and favorable safety in human dermal fibroblast (HDF) cells, highlighting its promising selectivity and low cytotoxicity toward normal cells.
Results
Selective anticancer activity
Image Credit: Rania Hamdy et al., in partnership with ELRIG (UK) Ltd.
Heatmap showing preferential cytotoxicity toward Bcl-2-expressing cells, with green indicating high potency (IC50 < 5 μM), yellow moderate potency (5–20 μM), and red low potency (≥ 20 μM).
Bcl-2 binding assay
Table 3. IC50 of the short-listed compounds as Bcl-2 inhibitor. Source: University of Sharjah
| Compound |
IC50 μM |
| R4 |
0.45 ± 0.025 |
| R14 |
0.25 ± 0.04 |
| R17 |
0.63 ± 0.09 |
| R23 |
0.54 ± 0.06 |
| R25 |
12.34 ± 0.57 |
| R27 |
1.81 ± 0.19 |
| Gossypol |
0.6 ± 0.09 |
| Venetoclax (ABT-199) |
0.038 ± 0.002 |
Compounds R4, R14, and R23 exhibited more potent Bcl-2 inhibition than gossypol, with lower IC50 values (0.25–0.54 μM vs. 0.60 μM).
Apoptosis assay
Image Credit: Rania Hamdy et al., in partnership with ELRIG (UK) Ltd.
R23 Induced Apoptosis and Cell Cycle Arrest at G1 Phase
ADMET prediction
Image Credit: Rania Hamdy et al., in partnership with ELRIG (UK) Ltd.
Bioavailability radar of ADME properties. The pink area indicates the preferred property range for compounds R4, R14, R17, and R23.
Computational modelling
Image Credit: Rania Hamdy et al., in partnership with ELRIG (UK) Ltd.
R4, R14, and R17, R23 exhibited favorable interactions within the Bcl-2 binding site, supporting its potential as a Bcl-2 inhibitor.
Molecular dynamic simulation
Image Credit: Rania Hamdy et al., in partnership with ELRIG (UK) Ltd.
MDs confirmed stability of R23 complex with the target protein with low RMSD fluctuation ranges
WaterMap analysis
Image Credit: Rania Hamdy et al., in partnership with ELRIG (UK) Ltd.
WaterMap analysis: (A) R4, (B) R14, and (C) R23. R23 exhibited most displaceable hydration sites and highest total ΔG, suggesting favorable interactions with Bcl-2 and potential as a Bcl-2 inhibitor.
R-Group analysis
Image Credit: Rania Hamdy et al., in partnership with ELRIG (UK) Ltd.
Heatmap analysis showed the variance activity with different R-groups. QSAR analysis highlighted that hydrophobicity significantly increased the activity.
Conclusion
- Potent Bcl-2 inhibition: Novel indole–triazole derivatives demonstrated selective anticancer activity against Bcl-2-expressing cancer cells.
- Superior binding affinity: R4, R14, and R23 exhibited stronger Bcl-2 inhibition than gossypol in ELISA assays.
- Apoptosis induction: R23 induced G1-phase cell cycle arrest and enhanced early and late apoptosis.
- Computational validation: R23 showed favorable Bcl-2 selectivity, hydration-site displacement, and stable binding during MD simulations.
- Favorable safety profile: R23 and R14 exhibited low cytotoxicity toward normal HDF cells, supported by favorable ADMET predictions.
- Promising lead candidate: R23 emerged as the most promising Bcl-2 inhibitor, warranting further preclinical evaluation.
References
Almehdi, A.M., et al. (2025). Next-generation Bcl-2 inhibitors: Design and evaluation of indolyl-triazole derivatives with anticancer potential. ChemMedChem, 20(21), p.e202500265. DOI:10.1002/cmdc.202500265. https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202500265.
About University of Sharjah
The University of Sharjah is licensed and our degree programs are accredited by the Commission for Academic Accreditation under the Ministry of Education's Higher Education Affairs division in the United Arab Emirates. Most of our programs have attained international accreditation.
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Last Updated: Oct 29, 2026