Pharmacological Control of Cell Fate via Centriole-Associated Determinants
DOI:
https://doi.org/10.65649/9m7y8r96Keywords:
Centriole, Cell Fate, PROTAC, PLK4 Inhibitors, Phase Separation, Cancer Stem Cells, Regenerative MedicineAbstract
The centriole has evolved from a structural microtubule-organizing center to a dynamic signaling hub that integrates mechanical, biochemical, and spatial information to regulate cell identity. Centriole-Associated Fate Determinants (CAFDs) comprise a diverse class of proteins—including transcription factors, signaling effectors, and structural regulators—whose physical interaction with the centriole governs their activity, stability, and inheritance. This review synthesizes recent advances in the pharmacological targeting of CAFD-centriole interactions as a strategy for precise intervention in cell fate decisions. We analyze four target classes: (1) direct CAFD-centriolar adaptor interfaces (YAP-AMOTL2-CEP83, LGN-NuMA, STAT3-centriole); (2) kinases regulating CAFD availability (PLK4, NEK2, GSK3β); (3) the ubiquitin-proteasome system at the centrosome (SCF^FBXW7^, COP9 signalosome, USP9X); and (4) liquid-liquid phase separation (LLPS) condensates that concentrate CAFDs within the pericentriolar material. Methodological platforms including PROTACs, peptidomimetics, allosteric modulators, and nanoparticle-based delivery systems are critically evaluated. PLK4 inhibitors represent the most clinically advanced approach, with RP-1664 having entered Phase 1 trials, though on-target toxicity and the need for biomarker-driven patient selection (e.g., TRIM37-amplified tumors) remain significant challenges. PROTAC technology offers unprecedented potential for eliminating oncogenic CAFDs, but achieving pool-specific degradation—selectively targeting the centriolar population while sparing essential nuclear or junctional pools—remains an unresolved hurdle. The LGN-NuMA complex, despite structural elucidation, is likely therapeutically intractable due to its essential role in all mitotic cells. LLPS modulation, while mechanistically illuminating, awaits discovery of centrosome-specific phase regulators. We conclude that the most realistic near-term applications lie in biomarker-selected oncology (PLK4/NEK2 inhibitors) and ex vivo stem cell manipulation, where controlled culture environments circumvent systemic delivery and toxicity challenges. Elegant in vivo regulation of specific CAFD pools awaits breakthroughs in targeted protein degradation, structural biology, and precision delivery technologies.
References
Banik, K., et al. (2025). Role of PLK4 inhibition in cancer therapy. Cancer and Metastasis Reviews, 44(2), 55.
Bertin Bioreagent. (2024). WP1130 product information. Bertin Bioreagent Catalog.
Carminati, M., Gallini, S., Pirovano, L., Alfieri, A., Bisi, S., & Mapelli, M. (2016). Concomitant binding of Afadin to LGN and F-actin directs planar spindle orientation. Nature Structural & Molecular Biology, 23(2), 155-163.
Carroll, T. D., Newton, I. P., Chen, Y., Blow, J. J., & Näthke, I. (2017). Lgr5+ intestinal stem cells reside in an unlicensed G1 phase. Journal of Cell Biology, 217(5), 1667-1685.
Cayman Chemical. (n.d.). Pitstop2 (CAS 1332879-52-3) product information. Cayman Chemical.
Chen, C., & Yamashita, Y. M. (2021). Centrosome-centric view of asymmetric stem cell division. Open Biology, 11(1), 200314.
Chen, C., Inaba, M., Venkei, Z. G., & Yamashita, Y. M. (2016). Klp10A, a stem cell-specific microtubule-depolymerizing kinesin, regulates asymmetric stem cell division. Developmental Cell, 39(1), 109-122.
Chen, C., Venkei, Z. G., & Yamashita, Y. M. (2020). Alms1a is a stem cell-specific regulator of centriole duplication in the Drosophila testis. eLife, 9, e59368.
Domínguez-Vigil, I. G., Banik, K., Baro, M., Contessa, J. N., & Hayman, T. J. (2025). PLK4 inhibition as a strategy to enhance non-small cell lung cancer radiosensitivity. Molecular Cancer Therapeutics, 24(9), 1350-1361.
Fernandes-Mariano, C., et al. (2025). Centrosome biogenesis and maintenance in homeostasis and disease. Current Opinion in Cell Biology, 94, 102485.
Fletcher, A., Clift, D., de Vries, E., Martinez Cuesta, S., Malcolm, T., Meghini, F., Chaerkady, R., Wang, J., Chiang, A., Weng, S. H. S., Tart, J., Wong, E., Donohoe, G., Rawlins, P., Gordon, E., Taylor, J. D., James, L., & Hunt, J. (2023). A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation. Nature Communications, 14(1), 7093.
Godinho, S. A., & Pellman, D. (2014). Causes and consequences of centrosome abnormalities in cancer. Philosophical Transactions of the Royal Society B: Biological Sciences, 369(1650), 20130467.
Gönczy, P. (2025). Critical constituents and assembly principles of centriole biogenesis in human cells. Nature Reviews Molecular Cell Biology. Advance online publication.
Guo, X., Liu, Q., Wang, G., Zhu, S., Gao, L., Cheng, W., Zhao, Y., & Luo, J. (2015). GSK3 inhibitors CHIR99021 and 6-bromoindirubin-3'-oxime inhibit microRNA maturation in mouse embryonic stem cells. Scientific Reports, 5, 8666.
Inaba, H., Goto, H., Kasahara, K., Kumamoto, K., Yonemura, S., Inoko, A., Yamano, S., Wanibuchi, H., He, D., Goshima, N., Kiyono, T., Hirotsune, S., & Inagaki, M. (2016). The Ndel1-Nde1 complex mediates dynein-dynactin-driven transport of trichoplein to the primary cilium. Molecular Biology of the Cell, 27(22), 3583-3593.
Jaba, T. (2022). Dasatinib and quercetin: short-term simultaneous administration yields senolytic effect in humans. Issues and Developments in Medicine and Medical Research Vol. 2, 22-31.
Janeček, M., Rossmann, M., Sharma, P., Emery, A., Huggins, D. J., Stockwell, S. R., Stokes, J. E., Tan, Y. S., Almeida, E. G., Hardwick, B., Narvaez, A. J., Hyvönen, M., Spring, D. R., McKenzie, G. J., & Venkitaraman, A. R. (2016). Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2. Scientific Reports, 6, 28528.
Kiyomitsu, T., & Cheeseman, I. M. (2013). Cortical dynein and asymmetric membrane elongation coordinately position the spindle in anaphase. Cell, 154(2), 391-402.
Levine, M. S., & Holland, A. J. (2018). The impact of mitotic errors on cell proliferation and tumorigenesis. Genes & Development, 32(9-10), 620-638.
Levine, M. S., & Holland, A. J. (2018). The impact of mitotic errors on cell proliferation and tumorigenesis. Genes & Development, 32(9-10), 620-638.
Liu, Y., Zhang, H., & Wang, J. (2025). Targeted protein degradation of Wnt/β-catenin signaling pathway: an effective strategy for cancer therapy. Journal of Translational Medicine, 23, 1145.
Liu, Y., Zhang, Y., & Wang, Z. (2024). Molecular insights and clinical implications for the tumor suppressor role of SCFFBXW7 E3 ubiquitin ligase. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1879(4), 189112.
Meitinger, F., Ohta, M., Lee, K. Y., Watanabe, S., Davis, R. L., Anzalone, A. V., Khabirova, E., & Desai, A. (2020). TRIM37 controls cancer-specific vulnerability to Plk4 inhibition. Nature, 585(7825), 447-452.
Nigg, E. A., & Holland, A. J. (2018). Once and only once: mechanisms of centriole duplication and their deregulation in disease. Nature Reviews Molecular Cell Biology, 19(5), 297-312.
Pan, Y., et al. (2025). Proteolysis targeting chimera, molecular glue degrader and hydrophobic tag tethering degrader for targeted protein degradation: Mechanisms, strategies and application. Bioorganic Chemistry, 161, 108491.
Paridaen, J. T., Wilsch-Bräuninger, M., & Huttner, W. B. (2013). Asymmetric inheritance of centrosome-associated primary cilium membrane directs ciliogenesis after cell division. Cell, 155(2), 333-344.
Peyre, E., Jaouen, F., Saadaoui, M., Haren, L., Merdes, A., Durbec, P., & Morin, X. (2011). A lateral belt of cortical LGN and NuMA guides mitotic spindle movements and planar division in neuroepithelial cells. Journal of Cell Biology, 193(1), 141-154.
Pirovano, L., Culurgioni, S., Carminati, M., et al. (2019). Hexameric NuMA:LGN structures promote multivalent interactions required for planar epithelial divisions. Nature Communications, 10, 2208.
Rellos, P., Ivins, F. J., Baxter, J. E., Pike, A., Nott, T. J., Parkinson, D. M., Das, S., Howell, S., Fedorov, O., Shen, Q. Y., Fry, A. M., Knapp, S., & Smerdon, S. J. (2007). Structure and regulation of the human Nek2 centrosomal kinase. Journal of Biological Chemistry, 282(9), 6833-6842.
Repare Therapeutics. (2024). Phase 1 trial of RP-1664 in participants with advanced solid tumors (LIONS). ClinicalTrials.gov, NCT06232408.
Shao, W., Yang, J., He, M., et al. (2020). Centrosome anchoring regulates progenitor properties and cortical formation. Nature, 580(7801), 106-112.
Shao, W., Yang, J., He, M., Yu, X. Y., Lee, C. H., Yang, Z., & Joyner, A. L. (2020). Centrosome anchoring regulates progenitor properties and cortical formation. Nature, 580(7801), 106-112.
Shin, B., & Kim, J. (2021). Generation and fates of supernumerary centrioles in dividing cells. Molecules and Cells, 44(10), 699-705.
Smiley, S. B., Yun, Y., Ayyagari, P., Shannon, H. E., Pollok, K. E., Vannier, M. W., Das, S. K., & Veronesi, M. C. (2021). Development of CD133 targeting multi-drug polymer micellar nanoparticles for glioblastoma - In vitro evaluation in glioblastoma stem cells. Pharmaceutical Research, 38(6), 1067-1079.
Springer. (2025). Table 1 Targeted therapy of the Hippo signalling pathway. Cancer Cell International, 25, 123.
Suri, A., Bailey, A. W., Tavares, M. T., et al. (2019). Evaluation of protein kinase inhibitors with PLK4 cross-over potential in a pre-clinical model of cancer. International Journal of Molecular Sciences, 20(9), 2112.
Tkemaladze, J. (2023). Reduction, proliferation, and differentiation defects of stem cells over time: a consequence of selective accumulation of old centrioles in the stem cells?. Molecular Biology Reports, 50(3), 2751-2761. DOI : https://pubmed.ncbi.nlm.nih.gov/36583780/
Tkemaladze, J. (2024). Editorial: Molecular mechanism of ageing and therapeutic advances through targeting glycative and oxidative stress. Front Pharmacol. 2024 Mar 6;14:1324446. DOI : 10.3389/fphar.2023.1324446. PMID: 38510429; PMCID: PMC10953819.
Tkemaladze, J. (2026). Old Centrioles Make Old Bodies. Annals of Rejuvenation Science, 1(1). DOI : https://doi.org/10.65649/yx9sn772
Tkemaladze, J. (2026). Visions of the Future. Longevity Horizon, 2(1). DOI : https://doi.org/10.65649/8be27s21
Tocris Bioscience. (n.d.). 1,6-Hexanediol product information. R&D Systems.
University Health Network. (2020). A Phase I dose escalation and expansion clinical trial of CFI-400945 in patients with advanced solid tumors. ClinicalTrials.gov.
Uzbekov, R., & Avidor-Reiss, T. (2020). Principal postulates of centrosomal biology: version 2020. Cells, 9(7), 1716.
Vallée, F., et al. (2025). Discovery of RP-1664: A first-in-class orally bioavailable, selective PLK4 inhibitor. Journal of Medicinal Chemistry, 68(11), 10631-10647.
Vanni, G., et al. (2025). Microtubule architecture connects AMOT stability to YAP/TAZ mechanotransduction and Hippo signalling. Nature Cell Biology, 27(10), 1725-1738.
Vanni, M., et al. (2025). Microtubule architecture connects AMOT stability to YAP/TAZ mechanotransduction and Hippo signalling. Nature Cell Biology, 27(10), 1725-1738.
Veitch, Z., et al. (2021). Safety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: a phase 1 dose-escalation trial. Journal of Clinical Oncology, 39(15_suppl), 3077.
Veitch, Z., et al. (2021). Safety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: a phase 1 dose-escalation trial. Journal of Clinical Oncology, 39(15_suppl), 3077.
Wang, L., Zhang, H., & Chen, J. (2025). In vitro evaluation of Verteporfin and exploration of TEAD palmitoylation inhibition in Piezo1–YAP/TAZ signaling and ECM remodeling. DOAJ, 15(3), 100456.
Wang, R., Ascanelli, C., Abdelbaki, A., et al. (2021). Selective targeting of non-centrosomal AURKA functions through use of a targeted protein degradation tool. Communications Biology, 4, 640.
Wang, R., Ascanelli, C., Abdelbaki, A., Fung, A., Rasmusson, T., Michaelides, I., Roberts, K., & Lindon, C. (2021). Selective targeting of non-centrosomal AURKA functions through use of a targeted protein degradation tool. Communications Biology, 4(1), 640.
Wang, R., Ascanelli, C., Abdelbaki, A., Fung, A., Rasmusson, T., Michaelides, I., Roberts, K., & Lindon, C. (2021). Selective targeting of non-centrosomal AURKA functions through use of a targeted protein degradation tool. Communications Biology, 4, 640.
Wang, W., Zhang, M., Wang, Z., Yin, Y., Jiang, X., Wang, H., Sun, Y., & Tang, B. Z. (2022). Genetically edited T-cell membrane coated AIEgen nanoparticles effectively prevents glioblastoma recurrence. Biomaterials, 293, 121981.
Wang, X., Tsai, J. W., Imai, J. H., Lian, W. N., Vallee, R. B., & Shi, S. H. (2009). Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature, 461(7266), 947-955.
Wang, Y., et al. (2025). Advances in peptide-based chimeric strategies for targeted protein degradation. Journal of Medicinal Chemistry, 68(24), 25708-25728.
Watts, C. A., Richards, F. M., Bender, A., Bond, P. J., Korb, O., Kern, O., Riddick, M., Owen, P., Myers, R. M., Raff, J., Gergely, F., Jodrell, D. I., & Ley, S. V. (2013). Design, synthesis, and biological evaluation of an allosteric inhibitor of HSET that targets cancer cells with supernumerary centrosomes. Chemistry & Biology, 20(11), 1399-1410.
Wong, Y. L., Anzola, J. V., Davis, R. L., et al. (2015). Reversible centriole depletion with an inhibitor of Polo-like kinase 4. Science, 348(6239), 1155-1160.
Wong, Y. L., Anzola, J. V., Davis, R. L., Yoon, M., Motamedi, A., Kroll, A., Seo, C. P., Hsia, J. E., Kim, S. K., Mitchell, J. W., Mitchell, B. J., Desai, A., Gahman, T. C., Shiau, A. K., & Oegema, K. (2015). Reversible centriole depletion with an inhibitor of Polo-like kinase 4. Science, 348(6239), 1155-1160.
Wong, Y. L., Kim, S. K., & Oegema, K. (2018). CFI-400945 is not a selective cellular PLK4 inhibitor. Proceedings of the National Academy of Sciences, 115(46), E10808-E10809.
Woodruff, J. B., Ferreira Gomes, B., Widlund, P. O., Mahamid, J., Honigmann, A., & Hyman, A. A. (2017). The centrosome is a selective condensate that nucleates microtubules by concentrating tubulin. Cell, 169(6), 1066-1077.
Xie, Y., & Chen, L. (2020). Protocol to identify centrosome-associated transcription factors during mitosis in mammalian cell lines. STAR Protocols, 2(3), 100495.
Yamashita, Y. M., Mahowald, A. P., Perlin, J. R., & Fuller, M. T. (2007). Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science, 315(5811), 518-521.
Yeh, H. W., et al. (2024). Cep57 regulates human centrosomes through multivalent interactions. Proceedings of the National Academy of Sciences, 121(26), e2401499121.
Yeow, Z. Y., Lambrus, B. G., Marlow, R., Zhan, K. H., Durin, M. A., Evans, L. T., Scott, P. M., Phan, T., Park, E., Ruiz, L. A., Moralli, D., Knight, E. G., Badder, L. M., Novo, D., Haider, S., Green, C. M., Tutt, A. N., Lord, C. J., Chapman, J. R., & Holland, A. J. (2020). Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer. Nature, 585(7825), 447-452.
Yu, S., et al. (2025). Molecular insights into AGS3's role in spindle orientation: a biochemical perspective. Journal of Molecular Cell Biology, 16(11), mjae049.
Zhang, Y., Wang, X., & Li, H. (2022). Centrosome defects in hematological malignancies: Molecular mechanisms and therapeutic insights. Blood Science, 4(3), 143-151.
Zhao, C., Wang, X., Zhang, Y., Li, J., & Chen, L. (2024). Lactoferrin/CD133 antibody conjugated nanostructured lipid carriers for dual targeting of blood-brain-barrier and glioblastoma stem cells. Biomedical Materials, 19(5), 055012.
Zheng, H., et al. (2024). Aurora-A condensation mediated by BuGZ aids its mitotic centrosome functions. iScience, 27(5), 109789.
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