CDK inhibitor

A CDK (cyclin-dependent kinase) inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance),[1] a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. Several compounds are in clinical trials.

This article is about the medical therapy. For the cell cycle protein, see Cyclin-dependent kinase inhibitor protein.

CDKs as cancer target
See also Ribociclib#Mechanism of action re: CDK4

In many human cancers, CDKs are overactive or CDK-inhibiting proteins are not functional.[2][3] Therefore, it is rational to target CDK function to prevent unregulated proliferation of cancer cells.

However, the validity of CDK as a cancer target should be carefully assessed because genetic studies have revealed that knockout of one specific type of CDK often does not affect proliferation of cells or has an effect only in specific tissue types. For example, most adult cells in mice proliferate normally even without both CDK4 and CDK2.[4]

Furthermore, specific CDKs are only active in certain periods of the cell cycle. Therefore, the pharmacokinetics and dosing schedule of the candidate compound must be carefully evaluated to maintain active concentration of the drug throughout the entire cell cycle.[5]

Types

Malumbres et al., categorized CDK inhibitors based on their target specificity:[5]

  • Broad CDK inhibitors: compounds targeting a broad spectrum of CDKs
  • Specific CDK inhibitors: compounds targeting a specific type of CDK
  • Multiple target inhibitors: compounds targeting CDKs as well as additional kinases such as VEGFR or PDGFR

Approved

Palbociclib (PD-0332991) (inhibitor of CDK4 and CDK6) (trade name IBRANCE) gave encouraging results in a phase II clinical trial on patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer.[6] The addition of PD-0332991 to letrozole trebled median time to disease progression to 26.1 months compared with 7.5 months for letrozole alone. The FDA granted it Accelerated Approval in Feb 2015.[7]

Ribociclib, an inhibitor of CDK4 and CDK6 (trade name KISQALI) , is US FDA approved in combination with letrozole for treatment of breast cancer in patients with a hormone receptor positive, HER2 negative advanced metastatic breast cancer.[8] A phase three clinical trial found that Ribocyclib administered in combination with letrozole increased the likelihood of progression free survival to 63% in the first 18 months of therapy versus 42% for letrozole alone.[9] Subsequent analysis demonstrated that patients treated with Ribociclib and letrozole showed a median progression-free survival of 25.3 months.[8]

Abemaciclib (LY2835219) (trade name Verzenio) acts as a selective inhibitor for CDK4 and CDK6.[10] In September 2017 the US FDA approved its use for "adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones".[11]

In clinical trials

There are more than 10 CDK inhibitor compounds that have gone through or currently ongoing clinical trials, as of 2009. Most of them are targeting multiple CDKs, but some are targeting specific CDKs. For example, P1446A-05 targets CDK4. Various types of cancers including leukemia, melanoma, solid tumors, and other types are being targeted. In some cases, very specific cancer types, such as 'melanoma positive for cyclin D1 expression' are targeted to maximize the efficacy.[12]

As of January 2016, Abemaciclib (LY2835219, CDK4/6 inhibitor, Eli Lily) is in two phase 3 trials for breast cancer. In March 2017, abemaciclib demonstrated superior progression-free survival over placebo plus fulvestrant in patients with estrogen receptor positive and HER2 negative advanced or metastatic breast cancer after the completion of the MONARCH 2 global Phase 3 clinical trial. In February 2018, the FDA approved abemaciclib (VERZENIO) in combination with an aromatase inhibitor as initial therapy for women with HR-positive, HER-2-negative metastatic breast cancer.[13]

As of March 2016, Ribociclib (LEE011, CDK4/6 inhibitor, Novartis/Astex) is in three phase 3 trials for breast cancer.[14] In Oct 2016 good results (increased PFS) were reported from the MONALEESA-2 trial in metastatic breast cancer.[15] In March 2018, the FDA approved ribociclib (Kiskali) in combination with an aromatase inhibitor as initial therapy for postmenopausal women with HR-positive, HER-2-negative advanced or metastatic breast cancer.[16]

As of February 2017, Trilaciclib (G1T28, CDK4/6 inhibitor, G1 Therapeutics) is in multiple phase 2 clinical trials.[17] The drug is being tested as a method for reducing the adverse effects of chemotherapy. In August 2019, Trilaciclib received Breakthrough therapy designation[18] for its ability to minimize chemotherapy-induced bone marrow suppression. As of August 2020, the drug is under FDA Priority review for small cell lung cancer with an application decision date of February 15, 2021.[19]

Other
  • Purvalanol A, Olomoucine II.[20]

See also

References
  1. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432871.htm
  2. Malumbres, M; Barbacid, M (2001). "To cycle or not to cycle: A critical decision in cancer". Nature Reviews Cancer. 1 (3): 222–31. doi:10.1038/35106065. PMID 11902577.
  3. Malumbres, M; Barbacid, M (2009). "Cell cycle, CDKs and cancer: A changing paradigm". Nature Reviews Cancer. 9 (3): 153–66. doi:10.1038/nrc2602. PMID 19238148.
  4. Barrière, C; Santamaría, D; Cerqueira, A; Galán, J; Martín, A; Ortega, S; Malumbres, M; Dubus, P; Barbacid, M (2007). "Mice thrive without Cdk4 and Cdk2". Molecular Oncology. 1 (1): 72–83. doi:10.1016/j.molonc.2007.03.001. PMC 5543859. PMID 19383288.
  5. Malumbres, M; Pevarello, P; Barbacid, M; Bischoff, J. R. (2008). "CDK inhibitors in cancer therapy: What is next?". Trends in Pharmacological Sciences. 29 (1): 16–21. doi:10.1016/j.tips.2007.10.012. PMID 18054800.
  6. "Novel Agent Extends Breast Cancer Time to Progression". 6 Dec 2012.
  7. "FDA Grants Palbociclib Accelerated Approval for Advanced Breast Cancer - National Cancer Institute". www.cancer.gov. 2015-02-11. Retrieved 2020-12-31.
  8. "Novartis Kisqali® (ribociclib, LEE011) receives FDA approval as first-line treatment for HR+/HER2- metastatic breast cancer in combination with any aromatase inhibitor". Novartis. Retrieved 12 September 2017.
  9. Hortobagyi, GN; Stemmer, SM; Burris, HA; Yap, YS; Sonke, GS; Paluch-Shimon, S; Campone, M; Blackwell, KL; André, F; Winer, EP; Janni, W; Verma, S; Conte, P; Arteaga, CL; Cameron, DA; Petrakova, K; Hart, LL; Villanueva, C; Chan, A; Jakobsen, E; Nusch, A; Burdaeva, O; Grischke, EM; Alba, E; Wist, E; Marschner, N; Favret, AM; Yardley, D; Bachelot, T; Tseng, LM; Blau, S; Xuan, F; Souami, F; Miller, M; Germa, C; Hirawat, S; O'Shaughnessy, J (3 November 2016). "Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer". The New England Journal of Medicine. 375 (18): 1738–1748. doi:10.1056/NEJMoa1609709. PMID 27717303.
  10. Lu, Janice (13 August 2015). "Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer". Journal of Hematology & Oncology. 8 (1): 98. doi:10.1186/s13045-015-0194-5. PMC 4534142. PMID 26264704.
  11. "FDA approves new treatment for certain advanced or metastatic breast cancers" (Press release). Food and Drug Administration. September 28, 2017.
  12. Lapenna, S; Giordano, A (2009). "Cell cycle kinases as therapeutic targets for cancer". Nature Reviews Drug Discovery. 8 (7): 547–66. doi:10.1038/nrd2907. PMID 19568282.
  13. Research, Center for Drug Evaluation and (2019-02-09). "FDA approves abemaciclib as initial therapy for HR-positive, HER2-negative metastatic breast cancer". FDA.
  14. phase 3 trials of LEE011
  15. Anti-CDK4/6 Boosts PFS in Metastatic Breast Cancer. Oct 2016
  16. Research, Center for Drug Evaluation and (2019-02-09). "Ribociclib (Kisqali)". FDA.
  17. Trilaciclib trials
  18. "Breakthrough Therapies | Friends of Cancer Research". friendsofcancerresearch.org. Retrieved 2020-12-28.
  19. staff, By. "FDA Grants Priority Review of Trilaciclib for Treating Small Cell Lung Cancer". www.uspharmacist.com. Retrieved 2020-12-28.
  20. Purvalanol A, Olomoucine II and Roscovitine Inhibit ABCB1 Transporter and Synergistically Potentiate Cytotoxic Effects of Daunorubicin In Vitro.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.