CDK inhibitor

src: molpharm.aspetjournals.org

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), a CDK4/6 inhibitor, in Feb 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. Several compounds are in clinical trials.

Video CDK inhibitor

CDKs as cancer target

In many human cancers, CDKs are overactive or CDK-inhibiting proteins are not functional. 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.

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.

See also Ribociclib#Mechanism re CDK4

Maps CDK inhibitor

Types

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

• 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

src: genesdev.cshlp.org

Approved

Ribociclib, an inhibitor of CDK 4 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. 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. Subsequent analysis demonstrated that patients treated with Ribociclib and letrozole showed a median progression-free survival of 25.3 months.

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. 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. 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".

src: genesdev.cshlp.org

On 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.

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. In Oct 2016 good results (increased PFS) were reported from the MONALEESA-2 trial in metastatic breast cancer.

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

src: atvb.ahajournals.org

Other

• Purvalanol A, Olomoucine II.

src: dev.biologists.org

See also

• Cyclin-dependent kinase § Medical significance

src: slideplayer.com

References

Source of article : Wikipedia