CDK inhibitor

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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.

CDKs as cancer target[edit]

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[edit]

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[edit]

Ribociclib, an inhibitor of CDK4 and CDK6, is US FDA approved in combination with letrozole for treatment of breast cancer in patients with an hormone receptor positive, HER2 negative advanced metastatic breast cancer.[6] 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.[7] Subsequent analysis demonstrated that patients treated with Ribociclib and letrozole showed a median progression-free survival of 25.3 months.[6]

Palbociclib (PD-0332991) (inhibitor of CDK4 and CDK6) gave encouraging results in a phase II clinical trial on patients with estrogen-positive, HER2-negative advanced breast cancer.[8] 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

Abemaciclib (LY2835219) (trade name Verzenio) acts as a selective inhibitor for CDK4 and CDK6.[9] 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".[10]

On clinical trials[edit]

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.[11]

As of January 2016, Abemaciclib (LY2835219) 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.

As of March 2016 Ribociclib (LEE011) (inhibitor of CDK4 and CDK6) is in three phase 3 trials for breast cancer.[12] In Oct 2016 good results (increased PFS) were reported from the MONALEESA-2 trial in metastatic breast cancer.[13]

As of February 2017 Trilaciclib (G1T28), (inhibitor of CDK4 and CDK6), is in phase 2 clinical trials.[14] e.g. for use to reduce side effects with chemotherapy.

Other[edit]

  • Purvalanol A, Olomoucine II.[15]

See also[edit]

References[edit]

  1. ^ http://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. PMID 19383288.
  5. ^ a b 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. ^ a b "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.
  7. ^ 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.
  8. ^ "Novel Agent Extends Breast Cancer Time to Progression". 6 Dec 2012.
  9. ^ 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). doi:10.1186/s13045-015-0194-5.
  10. ^ "FDA approves new treatment for certain advanced or metastatic breast cancers" (Press release). Food and Drug Administration. September 28, 2017.
  11. ^ 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.
  12. ^ phase 3 trials of LEE011
  13. ^ Anti-CDK4/6 Boosts PFS in Metastatic Breast Cancer. Oct 2016
  14. ^ Trilaciclib trials
  15. ^ Purvalanol A, Olomoucine II and Roscovitine Inhibit ABCB1 Transporter and Synergistically Potentiate Cytotoxic Effects of Daunorubicin In Vitro.