CDK inhibitor

Last updated

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. While there are multiple cyclin/CDK complexes regulating the cell cycle, CDK inhibitors targeting CDK4/6 have been the most successful; four CDK4/6 inhibitors have been FDA approved. [2] No inhibitors targeting other CDKs have been FDA approved, but several compounds are in clinical trials.

Contents

CDKs as cancer target

See also Ribociclib#Mechanism of action re: CDK4
The cyclin-CDK complexes associated with each phase of the cell cycle. These CDKs are the target of CDK inhibitors in order to cause cell cycle arrest and prevent unwanted cell proliferation. Cell cycle and CDK.jpg
The cyclin-CDK complexes associated with each phase of the cell cycle. These CDKs are the target of CDK inhibitors in order to cause cell cycle arrest and prevent unwanted cell proliferation.

The cell cycle is a highly regulated process governing cell division and is controlled by several cyclins and CDKs. Cyclins phosphorylate CDKs, forming complexes that stabilize them and allow them to enact their function. [3] While cyclins activate CDKs, there are other regulatory molecules that can inhibit their function. Under normal conditions, the activation and inhibition of CDK complexes controls the behavior of the cell at many important cell cycle checkpoints to regulate healthy division. However, this process can become dysregulated, leading to the uncontrolled division of cells known as cancer. [4] In fact, in many human cancers, CDKs are overactive or CDK-inhibiting proteins are not functional. [5] [6] CDK inhibitors as a therapy emerged from the idea that order could be restored to an overreactive cell cycle by inhibiting the CDKs whose activation drives the cell cycle forward. 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. [7]

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. [8]

Limitations

Another remaining question surrounding CDK inhibitors as a therapy is if certain cancers will evade or be resistant to treatment. One study showed that 20% of the patients being treated for metastatic ER+ HER2-breast cancer did not respond at all to treatment with a CDK4/6 inhibitor due to preexisting mutations allowing the cancer cells to continue proliferating despite treatment with the drug. [9] Other studies have shown this number to be as high as 30%. [10] Another study notes that the usefulness of CDK4/6 in the clinical may be limited by acquired drug resistance. In this study, treatment with CDK4/6 inhibitors in ER+ breast cancer and non-small cell lung carcinoma harboring KRAS mutations resulted in upregulation of cyclin D1, CDK4, and cyclin E1, negating the effects of administering the drug. [11]

Types

Malumbres et al., categorized CDK inhibitors based on their target specificity: [8]

Broad CDK inhibitors

Specific CDK inhibitors

Multiple Target Inhibitors

Approved

CDK4/CDK6 inhibitors

The current FDA approved drugs are all CDK4/6 inhibitors targeting CDK4 and CDK6, two enzymes that control the cell cycle checkpoint transition checkpoint from the G1 to the S phase of the cell cycle. These cell cycle inhibitors work by inducing cell cycle arrest at G1. [13]

Several drugs have been approved by the US FDA for HR-positive, HER2-negative breast cancer.

Palbociclib (PD-033299, trade name Ibrance) gave encouraging results in a phase II clinical trial on patients with HR-positive, HER2-negative advanced breast cancer. [14] 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. [15]

Ribociclib (LEE011, trade names Kisqali and Kryxana), is US FDA approved in combination with letrozole for treatment of breast cancer in patients with HR-positive, HER2-negative advanced metastatic breast cancer. [16] A phase three clinical trial found that ribociclib 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. [17] Subsequent analysis demonstrated that patients treated with ribociclib and letrozole showed a median progression-free survival of 25.3 months. [16]

Abemaciclib (LY2835219, trade name Verzenio) [18] was approved in September 2017 by the FDA 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". [19]

One drug has been FDA approved for mediating chemotherapy-induced side effects.

Trilaciclib (V03AF12, trade name Cosela) was approved in February 2021 to reduce chemotherapy-induced myelosuppression in patients with late-stage small-cell lung cancer (ES-SCLC). [20] However, there are active clinical trials evaluating the use of trilaciclib in other forms of cancer, including small cell lung cancer, breast cancer, and colorectal cancer. [21]

Dalpiciclib is approved in China for use in combination with fulvestrant for treatment of HR-positive, HER2-negative recurrent, or metastatic breast cancer in patients who have progressed after previous endocrine therapy. [22]

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. [23]

As of February 2017, trilaciclib (G1T28, CDK4/6 inhibitor, G1 Therapeutics) is in multiple phase II clinical trials. [24] The drug is being tested as a method for reducing the adverse effects of chemotherapy. In August 2019, trilaciclib received breakthrough therapy designation [25] for its ability to minimize chemotherapy-induced bone marrow suppression. As of August 2020, the drug was under Food and Drug Administration (FDA) priority review for small-cell lung cancer with an application decision date of February 15, 2021. [26] Atirmociclib is an investigational CDK4-specific inhibitor being developed by Pfizer for the treatment of various solid tumors, particularly hormone receptor-positive, HER2-negative breast cancer. [27] [28]

Although CDK4/6 inhibitors have had the most success, CDK inhibitors targeting other CDKs are also undergoing clinical trials. [29]

Combination therapies

Due to recurrent issues with CDK inhibitor resistance and non-responders, the current focus of many clinical trials includes examining the outcomes of administering CDK inhibitors in combination with other existing therapies. The interest in combined therapies is also in part due to the fact that CDK inhibitors halt the cell cycle to stop cancer growth, but they do not induce apoptosis to reduce tumor size. [10] Therefore, many clinical trials are interested in observing if there are better health outcomes by combining CDK inhibitors with other forms of therapy. For example, using a combination of Palbociclib (CDK4/6 inhibitor), Fulvestrant (estrogen receptor antagonist), and Avelumab (monoclonal antibody) for the treatment of metastatic ER+ HER- breast cancer is currently undergoing Phase II clinical trials. [32]

Other

Based on molecular docking results, Ligands-3, 5, 14, and 16 were screened among 17 different Pyrrolone-fused benzosuberene compounds as potent and specific inhibitors without any cross-reactivity against different CDK isoforms. Analysis of MD simulations and MM-PBSA studies, revealed the binding energy profiles of all the selected complexes. Selected ligands performed better than the experimental drug candidate (Roscovitine). Ligands-3 and 14 show specificity for CDK7 and Ligands-5 and 16 were specific against CDK9. These ligands are expected to possess lower risk of side effects due to their natural origin. [34]

Interpretation of dynamic simulations and binding free energy studies unveiled that Ligand2 (Out of 17 in-house synthesized pyrrolone-fused benzosuberene (PBS) compounds) has a stable and equivalent free energy to Flavopiridol, SU9516, and CVT-313 inhibitors. Ligand2 scrutinized as a selective inhibitor of CDK2 without off-target binding (CDK1 and CDK9) based on ligand efficiency and binding affinity. [35]

Graphical abstract of CDK2 CDK2-Selective inhibitor.png
Graphical abstract of CDK2

See also

References

  1. ↑ "FDA approves Ibrance for postmenopausal women with advanced breast cancer". Food and Drug Administration . Archived from the original on 2018-01-26. Retrieved 2019-12-16.
  2. ↑ Mughal, Muhammad Jameel; Bhadresha, Kinjal; Kwok, Hang Fai (2023-01-01). "CDK inhibitors from past to present: A new wave of cancer therapy". Seminars in Cancer Biology. 88: 106–122. doi: 10.1016/j.semcancer.2022.12.006 . ISSN   1044-579X. PMID   36565895.
  3. ↑ Ding, Lei; Cao, Jiaqi; Lin, Wen; Chen, Hongjian; Xiong, Xianhui; Ao, Hongshun; Yu, Min; Lin, Jie; Cui, Qinghua (2020-03-13). "The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer". International Journal of Molecular Sciences. 21 (6): 1960. doi: 10.3390/ijms21061960 . ISSN   1422-0067. PMC   7139603 . PMID   32183020.
  4. ↑ Malumbres, Marcos; Barbacid, Mariano (March 2009). "Cell cycle, CDKs and cancer: a changing paradigm" . Nature Reviews Cancer. 9 (3): 153–166. doi:10.1038/nrc2602. ISSN   1474-1768. PMID   19238148. S2CID   2613411.
  5. ↑ 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. S2CID   1967666.
  6. ↑ 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. S2CID   2613411.
  7. ↑ 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.
  8. 1 2 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.
  9. ↑ Scheidemann, Erin R.; Shajahan-Haq, Ayesha N. (2021-11-14). "Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer". International Journal of Molecular Sciences. 22 (22): 12292. doi: 10.3390/ijms222212292 . ISSN   1422-0067. PMC   8625090 . PMID   34830174.{{cite journal}}: CS1 maint: article number as page number (link)
  10. 1 2 Rampioni Vinciguerra, Gian Luca; Sonego, Maura; Segatto, Ilenia; Dall’Acqua, Alessandra; Vecchione, Andrea; Baldassarre, Gustavo; Belletti, Barbara (2022-05-27). "CDK4/6 Inhibitors in Combination Therapies: Better in Company Than Alone: A Mini Review". Frontiers in Oncology. 12 891580. doi: 10.3389/fonc.2022.891580 . ISSN   2234-943X. PMC   9197541 . PMID   35712501.
  11. ↑ Kong, Tim; Xue, Yibo; Cencic, Regina; Zhu, Xianbing; Monast, Anie; Fu, Zheng; Pilon, Virginie; Sangwan, Veena; Guiot, Marie-Christine; Foulkes, William D.; Porco, John A.; Park, Morag; Pelletier, Jerry; Huang, Sidong (November 2019). "eIF4A Inhibitors Suppress Cell-Cycle Feedback Response and Acquired Resistance to CDK4/6 Inhibition in Cancer". Molecular Cancer Therapeutics. 18 (11): 2158–2170. doi:10.1158/1535-7163.MCT-19-0162. ISSN   1535-7163. PMC   7132330 . PMID   31395685.
  12. 1 2 3 Zhang, Mengna; Zhang, Lingxian; Hei, Ruoxuan; Li, Xiao; Cai, Haonan; Wu, Xuan; Zheng, Qiping; Cai, Cheguo (2021-05-15). "CDK inhibitors in cancer therapy, an overview of recent development". American Journal of Cancer Research. 11 (5): 1913–1935. ISSN   2156-6976. PMC   8167670 . PMID   34094661.
  13. ↑ Goel, Shom; DeCristo, Molly J.; McAllister, Sandra S.; Zhao, Jean J. (November 2018). "CDK4/6 inhibition in cancer: beyond cell cycle arrest". Trends in Cell Biology. 28 (11): 911–925. doi:10.1016/j.tcb.2018.07.002. ISSN   0962-8924. PMC   6689321 . PMID   30061045.
  14. ↑ "Novel Agent Extends Breast Cancer Time to Progression". 6 Dec 2012.
  15. ↑ "FDA Grants Palbociclib Accelerated Approval for Advanced Breast Cancer - National Cancer Institute". www.cancer.gov. 2015-02-11. Retrieved 2020-12-31.
  16. 1 2 "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.[ permanent dead link ]
  17. ↑ 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 . hdl: 11577/3219743 . PMID   27717303.
  18. ↑ 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.
  19. ↑ "FDA approves new treatment for certain advanced or metastatic breast cancers" (Press release). U.S. Food and Drug Administration (FDA). September 28, 2017. Archived from the original on December 11, 2019.
  20. ↑ Powell, Kerrington; Prasad, V (2021-08-19). "Concerning FDA approval of trilaciclib (Cosela) in extensive-stage small-cell lung cancer". Translational Oncology. 14 (11): 101206. doi:10.1016/j.tranon.2021.101206. ISSN   1936-5233. PMC   8379686 . PMID   34419683.{{cite journal}}: CS1 maint: article number as page number (link)
  21. ↑ Dhillon, Sohita (2021-05-01). "Trilaciclib: First Approval" . Drugs. 81 (7): 867–874. doi:10.1007/s40265-021-01508-y. ISSN   1179-1950. PMID   33861388. S2CID   233258487.
  22. ↑ "Dalpiciclib in Combination with Letrozole or Anastrozole Significantly Improved Progression-free Survival in Systemic Treatment-naive, HR-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer". hengrui.com.
  23. ↑ 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. S2CID   7417169.
  24. ↑ Trilaciclib trials
  25. ↑ "Breakthrough Therapies". Friends of Cancer Research. Retrieved 2020-12-28.
  26. ↑ staff, By. "FDA Grants Priority Review of Trilaciclib for Treating Small Cell Lung Cancer". www.uspharmacist.com. Retrieved 2020-12-28.
  27. ↑ Pfizer (2025-08-12). A PHASE 1/2A DOSE ESCALATION AND EXPANSION STUDY TO EVALUATE SAFETY, TOLERABILITY, PHARMACOKINETIC, PHARMACODYNAMIC, AND ANTI-TUMOR ACTIVITY OF PF-07248144 IN PARTICIPANTS WITH ADVANCED OR METASTATIC SOLID TUMORS (Report). clinicaltrials.gov.
  28. ↑ Pfizer (2025-02-02). A PHASE 1/2A STUDY EVALUATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND ANTI-TUMOR ACTIVITY OF PF-07220060 AS A SINGLE AGENT AND AS PART OF COMBINATION THERAPY IN PARTICIPANTS WITH ADVANCED SOLID TUMORS (Report). clinicaltrials.gov.
  29. 1 2 Łukasik, Paweł; Baranowska-Bosiacka, Irena; Kulczycka, Katarzyna; Gutowska, Izabela (2021-03-10). "Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action". International Journal of Molecular Sciences. 22 (6): 2806. doi: 10.3390/ijms22062806 . ISSN   1422-0067. PMC   8001317 . PMID   33802080.
  30. ↑ "CTG Labs - NCBI". clinicaltrials.gov. 11 October 2021. Retrieved 2023-12-14.
  31. ↑ "CTG Labs - NCBI". clinicaltrials.gov. Retrieved 2023-12-14.
  32. ↑ "CTG Labs - NCBI". clinicaltrials.gov. Retrieved 2023-12-14.
  33. ↑ Purvalanol A, Olomoucine II and Roscovitine Inhibit ABCB1 Transporter and Synergistically Potentiate Cytotoxic Effects of Daunorubicin In Vitro.
  34. ↑ Singh R, Bhardwaj VK, Das P, Purohit R (November 2019). "Natural analogues inhibiting selective cyclin-dependent kinase protein isoforms: a computational perspective". Journal of Biomolecular Structure and Dynamics. 38 (17): 5126–5135. doi:10.1080/07391102.2019.1696709. PMID   3176087. S2CID   208276454.
  35. 1 2 Singh R, Bhardwaj VK, Sharma J, Das P, Purohit R (March 2021). "Identification of selective cyclin-dependent kinase 2 inhibitor from the library of pyrrolone-fused benzosuberene compounds: an in silico exploration". Journal of Biomolecular Structure and Dynamics. 40 (17): 7693–7701. doi:10.1080/07391102.2021.1900918. PMID   33749525. S2CID   232309609.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.