CDK inhibitor

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.

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.

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.

[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".

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).

[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.

In August 2019, trilaciclib received breakthrough therapy designation[25] for its ability to minimize chemotherapy-induced bone marrow suppression.

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.

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.

[30] 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.

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.
Graphical abstract of CDK2 [ 33 ]