XYLOKETAL DERIVATIVES FROM XYLARIA SP. AS STRUCTURAL LEADS FOR DUAL MYC/BCL2 AXIS MODULATION FOR DOUBLE-HIT HIGH-GRADE B-CELL LYMPHOMA: A DOCKING-BASED INVESTIGATION
DOI:
https://doi.org/10.36526/jc.v8i1.7402Keywords:
BCL2 inhibition, MYC/MAX, Xyloketal derivatives, LymphomaAbstract
High-grade B-cell lymphoma with concurrent MYC and BCL2 rearrangements, known as double-hit lymphoma, shows rapid tumor growth, strong resistance to apoptosis, and poor response to current therapies, largely because available treatments fail to target both oncogenic drivers at once. This study aimed to identify potential dual modulators of the MYC/BCL2 axis by evaluating xyloketal derivatives using a structure-based pharmacoinformatic approach. A total of twenty-one natural and semi-synthetic xyloketal compounds were prepared and analyzed through molecular docking against BCL2 at the BH3-binding groove (PDB: 4MAN) and the MYC/MAX heterodimer at the leucine zipper interface (PDB: 1NKP). Binding affinity, interaction profiles, and structure–activity relationships were examined using AutoDock Vina and Discovery Studio. The results showed that Xyloketal A achieved the strongest BCL2 binding affinity (−9.1 kcal/mol) while maintaining stable interactions with the MYC/MAX interface (−7.0 kcal/mol), supported by hydrogen bonding with Arg143 and Asp108 and hydrophobic contacts within the BH3 groove. Xyloketal J displayed the highest MYC/MAX affinity (−7.4 kcal/mol) with consistent BCL2 engagement, indicating a MYC-biased but still dual-target profile. Several derivatives, including Xyloketal A, Xyloketal J, and Xyloketal B cinnamyl ether, demonstrated balanced activity across both targets. These findings confirm that xyloketal scaffolds can engage both the BCL2 hydrophobic pocket and the MYC/MAX protein–protein interface, suggesting their potential as dual-target inhibitors. This study provides a clear computational foundation for the design and optimization of multi-target therapeutics aimed at overcoming the aggressive biology of double-hit high-grade B-cell lymphoma.
References
Alaggio, R., Amador, C., Anagnostopoulos, I., Attygalle, A. D., Araujo, I. B. d. O., Berti, E., . . . Calaminici, M. (2022). The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia, 36(7), 1720-1748.
Badria, F. A., De Filippis, B., El-Magd, M. A., Elbadawi, M. M., Hamdi, A., & Elgazar, A. A. (2025). Editorial: Multi-target drug discovery and design for complex health disorders. Frontiers in Pharmacology, Volume 16 - 2025.
Brambila, B., Martelli, A. C. F. S., Barcelos, M. P., Antão, S. C., da Silva, C. H. T. P., & Novo-Mansur, M. T. M. (2023). Protein–protein interaction for drug discovery. In Trends and Innovations in Energetic Sources, Functional Compounds and Biotechnology: Science, Simulation, Experiments (pp. 255-269): Springer.
Campo, E., Jaffe, E. S., Cook, J. R., Quintanilla-Martinez, L., Swerdlow, S. H., Anderson, K. C., . . . Dirnhofer, S. (2022). The international consensus classification of mature lymphoid neoplasms: a report from the clinical advisory committee. Blood, The Journal of the American Society of Hematology, 140(11), 1229-1253.
Casacuberta-Serra, S., González-Larreategui, Í., Capitán-Leo, D., & Soucek, L. (2024). MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer. Signal Transduction and Targeted Therapy, 9(1), 205.
Chen, S., Cai, R., Liu, Z., Cui, H., & She, Z. (2022). Secondary metabolites from mangrove-associated fungi: Source, chemistry and bioactivities. Natural product reports, 39(3), 560-595.
Chen, T., Shu, X., Zhou, H., Beckford, F. A., & Misir, M. (2023). Algorithm selection for protein–ligand docking: strategies and analysis on ACE. Scientific Reports, 13(1), 8219.
Chen, W., Yu, M., Chen, S., Gong, T., Xie, L., Liu, J., . . . Zheng, C. (2024). Structures and biological activities of secondary metabolites from Xylaria spp. Journal of Fungi, 10(3), 190.
Croce, C. M., Vaux, D., Strasser, A., Opferman, J. T., Czabotar, P. E., & Fesik, S. W. (2025). The BCL-2 protein family: from discovery to drug development. Cell Death & Differentiation, 1-13.
Dhanasekaran, R., Deutzmann, A., Mahauad-Fernandez, W. D., Hansen, A. S., Gouw, A. M., & Felsher, D. W. (2022). The MYC oncogene—the grand orchestrator of cancer growth and immune evasion. Nature reviews Clinical oncology, 19(1), 23-36.
Dhimitriu, R., Tsimpili, H., & Zoidis, G. (2025). Key breakthroughs in small molecule MYC inhibitors. In (Vol. 17, pp. 1097-1100): Taylor & Francis.
Donati, G., & Amati, B. (2022). MYC and therapy resistance in cancer: risks and opportunities. Molecular oncology, 16(21), 3828-3854.
Edaibis, R., Akel, R., & Shin, J. A. (2025). Beyond small molecules: advancing MYC-targeted cancer therapies through protein engineering. Transcription, 16(1), 67-85.
Gong, H., Bandura, J., Wang, G.-L., Feng, Z.-P., & Sun, H.-S. (2022). Xyloketal B: A marine compound with medicinal potential. Pharmacology & Therapeutics, 230, 107963.
Ji, T., Margulis, B. A., Wang, Z., Song, T., Guo, Y., Pan, H., & Zhang, Z. (2022). Structure-Based Design and Structure-Activity Relationship Analysis of Small Molecules Inhibiting Bcl-2 Family Members. Pharmaceutical Chemistry Journal, 56(3), 329-338. doi:10.1007/s11094-022-02639-6
Kater, A. P., Arslan, Ö., Demirkan, F., Herishanu, Y., Ferhanoglu, B., Diaz, M. G., . . . Rossi, D. (2024). Activity of venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia: analysis of the VENICE-1 multicentre, open-label, single-arm, phase 3b trial. The Lancet Oncology, 25(4), 463-473.
King, L. E., Hohorst, L., & García-Sáez, A. J. (2023). Expanding roles of BCL-2 proteins in apoptosis execution and beyond. Journal of cell science, 136(22), jcs260790.
Kumjan, S., Satayasoontorn, K., Lawongsa, K., & Laoruangroj, C. (2025). Prognostic outcomes of diffuse large B-cell lymphoma patients with myelocytomatosis oncogene (MYC) and B-cell lymphoma 2 (BCL2) co-expression. Journal of Hematopathology, 18(1), 1-10.
Lai, H., Wang, T., Sirelkhatim, H., Eaton, J., Huang, H., Rees, B., . . . Tibo, A. Improving protein-ligand complex generation with force field guidance.
Liu, L., Mo, W., Chen, M., Qu, Y., Wang, P., Liang, Y., & Yan, X. (2024). Targeted inhibition of DHODH is synergistic with BCL2 blockade in HGBCL with concurrent MYC and BCL2 rearrangement. BMC cancer, 24(1), 761.
Mukherjee, N., Sheetz, J., & Shellman, Y. G. (2025). Targeting the BCL2 Family: Advances and Challenges in BH3 Mimetic-Based Therapies. International journal of molecular sciences, 26(20), 9859.
Olbromski, P. J., Bogacz, A., Bukowska, M., Kamiński, A., Moszyński, R., Pawlik, P., . . . Czerny, B. (2023). Analysis of the Polymorphisms and Expression Levels of the BCL2, BAX and c-MYC Genes in Patients with Ovarian Cancer. International journal of molecular sciences, 24(22), 16309.
Qian, S., Wei, Z., Yang, W., Huang, J., Yang, Y., & Wang, J. (2022). The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Frontiers in Oncology, Volume 12 - 2022.
Schutz, S., Bergsdorf, C., Hanni-Holzinger, S., Lingel, A., Renatus, M., Gossert, A. D., & Jahnke, W. (2024). Intrinsically disordered regions in the transcription factor MYC: MAX modulate DNA binding via intramolecular interactions. Biochemistry, 63(4), 498-511.
Somasundaram, E., & Abramson, J. S. (2025). Double hit lymphoma: contemporary understanding and practices. Leukemia & Lymphoma, 66(1), 26-33.
Song, Z., Li, X., She, C., Wu, P., Xu, P., Xu, W., . . . Zhang, J. (2025). C-MYC and BCL2 as prognostic markers in diffuse large B-cell lymphoma: a systematic review and meta-analysis.
Tang, S., Ding, J., Zhu, X., Wang, Z., Zhao, H., & Wu, J. (2024). Vina-GPU 2.1: towards further optimizing docking speed and precision of AutoDock Vina and its derivatives. IEEE/ACM Transactions on Computational Biology and Bioinformatics.
Taylor, G., Davies, I., Wilson, J., & Thomas, S. (2023). Targeting Protein-Protein Interactions in Cancer Therapy: Rational Design and Mechanistic Insights into Small-Molecule Inhibitors.
Uchida, A., Isobe, Y., Asano, J., Uemura, Y., Hoshikawa, M., Takagi, M., & Miura, I. (2018). Targeting BCL2 with venetoclax is a promising therapeutic strategy for “double-proteinexpression” lymphoma with MYC and BCL2 rearrangements. Haematologica, 104(7), 1417.
Vom Stein, A. F., & Frenzel, L. P. (2025). Understanding and targeting BCL2-inhibitor resistance in chronic lymphocytic leukemia. Hematology/Oncology Clinics, 39(5), 965-979.
Wang, Z., Xu, S., Fang, S., Cong, L., Dai, L., Huang, W., . . . Wang, J. (2024). An economical, high-throughput protein-protein interaction modulator drug screening technique based on surface-enhanced Raman scattering. Sensors and Actuators B: Chemical, 410, 135683.
Wei, H., Wang, H., Wang, G., Qu, L., Jiang, L., Dai, S., . . . Li, Y. (2023). Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity. Nature Communications, 14(1), 4300.
Xu, J., Dong, X., Huang, D. C. S., Xu, P., Zhao, Q., & Chen, B. (2023a). Current Advances and Future Strategies for BCL-2 Inhibitors: Potent Weapons against Cancers. Cancers, 15(20), 4957. doi:10.3390/cancers15204957
Xu, J., Dong, X., Huang, D. C. S., Xu, P., Zhao, Q., & Chen, B. (2023b). Current advances and future strategies for BCL-2 inhibitors: potent weapons against cancers. Cancers, 15(20), 4957.
Yuan, D., Li, G., Yu, L., Jiang, Y., Shi, Y., Chen, Q., . . . Deng, M. (2021). CS2164 and venetoclax show synergistic antitumoral activities in high grade B-cell lymphomas with MYC and BCL2 rearrangements. Frontiers in Oncology, 11, 618908.
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