Review Abemaciclib: Senyawa Inhibitor Cyclin-Dependent Kinase 4, Generasi Ketiga Obat Kanker Payudara

https://doi.org/10.22146/jpmmpi.v2i1.68253

Viviane Annisa(1*)

(1) Fakultas Farmasi, Universitas Gadjah Mada
(*) Corresponding Author

Abstract


Abemaciclib merupakan inhibitor CDK generasi ketiga sebagai obat kanker payudara. Mekanisme aksi Abemaciclib dengan menghambat Cyclin-dependent kinase 4 (CDK4) dan 6 (CDK6) pada ikatan ATP dari CDK4 dan CDK6. Generasi pertama inhibitor CDK tidak selektif terhadap CKD4 dan CDK6 yang memiliki toksisitas yang sangat tinggi serta efikasi yang rendah, contohnya: Flavopiridol, Seliciclib, Dinaciclib, dan Milciclin, sedangkan generasi kedua didesain agar lebih selektif terhadap CDK2 dan CDK4, namun masih memiliki masalah toksisitas, contohnya: Dinaciclib. Generasi ketiga menunjukkan selektifitas yang lebih tinggi dibandingkan dengan generasi sebelumnya dan dapat meningkatkan efektivitas serta menurunkan efek sampingnya, contohnya: Abemaciclib, Ribociclib, dan Palbociclib. Jika dibandingkan dengan Palbociclib dan Ribociclib, Abemaciclib memiliki selektivitas yang lebih tinggi pada CDK4. Studi awal tentang Structur-Activity Relationship (SAR) dari derivat amina diheteroaromatik sebagai inhibitor CDK4/6 menunjukkan bahwa amino pyrimidine dan amino pyridine berperan menjaga aktivitas enzimatik dan seluler. Analog tetrahydronaphthyridine didesain untuk meningkatkan farmakokinetik dari Abemaciclib yang lebih baik. Atom deuterium (D) yang memiliki posisi berbeda dapat menambah stabilitas metabolik Abemaciclib. Terjadi peningkatan 11-45% terhadap stabilitas metabolik yang ditunjukkan dengan nilai waktu paruh (t1/2) yang lebih tinggi.

Kata kunci : Abemaciclib; Inhibitor CDK4; Inhibitor CDK6; SAR




References

Alagpulinsa, D. A., Ayyadevara, S., Yaccoby, S., & Reis, R. J. S. (2017). A cyclin-dependent kinase inhibitor, dinaciclib, impairs homologous recombination and sensitizes multiple myeloma cells to PARP inhibition. Mol Cancer Ther., 15(2), 241–250. https://doi.org/10.1158/1535-7163.MCT-15-0660 Annamaria Cimini,Michele d’Angelo,Elisabetta Benedetti,Barbara D’Angelo,Giulio Laurenti,Andrea Antonosante,Loredana Cristiano,Antonella Di Mambro,Marcella Barbarino,Vanessa Castelli,Benedetta Cinque,Maria Grazia Cifone,Rodolfo Ippoliti,Francesca Pentimall, A. G. (2016). Flavopiridol: An Old Drug With New Perspectives? Implication for Development of New Drugs. Journal of Cellular Physiology, 232(2), 312–322. https://doi.org/https://doi.org/10.1002/jcp.25421 Asghar, U., Witkiewicz, A. K., Turner, N. C., & Knudsen, E. S. (2015). The history and future of targeting cyclin-dependent kinases in cancer therapy. Nature Reviews Drug Discovery, 14, 130–146. https://www.nature.com/articles/nrd4504 Caldon, C. E., Daly, R. J., Sutherland, R. L., & Musgrove, E. A. (2006). Cell cycle control in breast cancer cells. In Journal of Cellular Biochemistry (Vol. 97, Issue 2, pp. 261–274). https://doi.org/10.1002/jcb.20690 Corona, S.P., & Generali, D. (2018). Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2− advanced breast cancer. Drug Design, Development and Therapy, 12, 321–330. https://doi.org/10.1080/14656566.2018.1448787% FDA. (2017). VERZENIO (Abemaciclib Tablet) Initial U.S. Aprroval. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208716s000lbl.pdf Flick, A. C., Leverett, C. A., Ding, H. X., McInturff, E., Fink, S. J., Helal, C. J., & O’Donnell, C. J. (2019). Synthetic Approaches to the New Drugs Approved during 2017. Journal of Medicinal Chemistry, 62(16), 7340–7382. https://doi.org/10.1021/acs.jmedchem.9b00196 Goetz, M., Toi, M., Campone, M., & Al., E. (2017). MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 35(32), 3638–3646. https://doi.org/10.1200/jco.2017.75.6155 Johnson, A., & Skotheim, J. M. (2013). Start and the restriction point. Curr Opin Cell Biol, 25(6), 717–723. https://doi.org/doi: 10.1016/j.ceb.2013.07.010. Epub Kwapisz D. (2017). Cyclin-dependent kinase 4/6 inhibitors in breast cancer: palbociclib, ribociclib, and abemaciclib. Breast Cancer Res Treat, 166(1), 41–54. https://doi.org/10.1007/s10549-017-4385-3 Lange, C. A., & Yee, D. (2011). Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer. Endocrine-Related Cancer, 18(2011), 19–24. Maria Jose Lallena, Karsten Boehnke, Raquel Torres, Ana Hermoso, Joaquin Amat, Bruna Calsina, Alfonso De Dios, Sean Buchanan, Jian Du, Richard Paul Beckmann, X. G. and A. M. (2015). In-vitro characterization of Abemaciclib pharmacology in ER+ breast cancer cell lines. Proceedings of the 106th Annual Meeting of the American Association for Cancer Research. https://doi.org/10.1158/1538-7445.AM2015-3101 McCartney, A., Moretti, E., Sanna, G., Pestrin, M., Risi, E., Malorni, L., Biganzoli, L., & Di Leo, A. (2018). The role of abemaciclib in treatment of advanced breast cancer. In Therapeutic Advances in Medical Oncology (Vol. 10). https://doi.org/10.1177/1758835918776925 Musgrove, E. A., Caldon, C. E., Barraclough, J., Stone, A., & Sutherland, R. L. (2011). Cyclin D as a therapeutic target in cancer. Nat Rev Cancer, 11(8), 558–572. https://doi.org/10.1038/nrc3090 N, D. (1998). The regulation of E2F by pRB-family proteins. Genes Dev, 12(15), 2245–2262. https://doi.org/doi: 10.1101/gad.12.15.2245 Poratti, M., & Marzaro, G. (2019). Third-generation CDK inhibitors: A review on the synthesis and binding modes of Palbociclib, Ribociclib and Abemaciclib. European Journal of Medicinal Chemistry, 172, 143–153. https://doi.org/10.1016/j.ejmech.2019.03.064 Sandrine Aspeslagh, Kunwar Shailubhai, Rastilav Bahleda, Anas Gazzah, Andréa Varga, Antoine Hollebecque, Christophe Massard, Anna Spreafico, Michele Reni, J.-C. S. (2017). Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors. Cancer Chemother Pharmacol, 79(6), 1257–1265. https://doi.org/DOI: 10.1007/s00280-017-3303-z Vella, S., Tavanti, E., Hattinger, C. M., Fanelli, M., Versteeg, R., Koster, J., Picci, P., & Serra, M. (2016). Targeting CDKs with roscovitine increases sensitivity to DNA damaging drugs of human osteosarcoma cells. In PLoS ONE (Vol. 11, Issue 11). https://doi.org/10.1371/journal.pone.0166233 Zha, C., Deng, W., Fu, Y., Tang, S., Lan, X., Ye, Y., Su, Y., Jiang, L., Chen, Y., Huang, Y., Ding, J., Geng, M., Huang, M., & Wan, H. (2018). Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy. European Journal of Medicinal Chemistry, 148, 140–153. https://doi.org/10.1016/j.ejmech.2018.02.022



DOI: https://doi.org/10.22146/jpmmpi.v2i1.68253

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Jurnal ini diterbitkan oleh:

Bidang Jurnal Paradigma Himpunan Mahasiswa Pascasarjana (HMP UGM) Universitas Gadjah Mada

69PF+FWC, Pogung Kidul, Pogung Kidul, Sinduadi, Kec. Mlati, Kabupaten Sleman, Daerah Istimewa Yogyakarta, Indonesia

Dengan dukungan dari:

Direktorat Kemahasiswaan Universitas Gadjah Mada
Gedung Pusat UGM, Lantai 1 Sayap Utara, Bulaksumur, Yogyakarta, Indonesia