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Review
. 2024 Nov 13;29(22):5334.
doi: 10.3390/molecules29225334.

Palbociclib as an Antitumor Drug: A License to Kill

Agnieszka Łupicka-Słowik  1 , Federica Cossu  2 , Marcin Sieńczyk  1
Affiliations
Review

Palbociclib as an Antitumor Drug: A License to Kill

Agnieszka Łupicka-Słowik et al. Molecules. .

Abstract

Neoplastic cells are characterized by uncontrolled cell divisions caused by cell cycle dysregulation. Key regulatory proteins governing the transition from the G1 to the S phase are the CDK4 and CDK6 kinases, which are controlled by D-type cyclins. The CDK4/6 kinases enable the use of these proteins as targets for anticancer therapy because they prevent the growth and the development of malignant cells by inhibiting their activity. This paper surveys the clinical trial results concerning palbociclib, the first in-class FDA-approved anticancer drug for hormone-dependent breast cancer. It discusses the therapeutic applications in breast cancer as well as in solid tumors and hematopoietic malignancies. Additionally, the paper presents an analysis of palbociclib resistance acquired during therapy and explores new approaches, such as modifications to palbociclib that enhance its desired activity or open up new therapeutic possibilities (PROTACs).

Keywords: PROTAC; SNIPERS; TNBC; antitumor; cyclin-dependent kinases; palbociclib; targeted therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
General mechanism of action of CDK4/6 in cell cycle control. AKT—protein kinase B, CDK4/6—cyclin dependent kinase 4 and 6, E2F—transcription factor family, ER—estrogen receptor, mTOR—mammalian target of rapamycin, PI3K—phosphoinositide 3-kinase, and Rb—retinoblastoma [2]. Created in BioRender. Sienczyk, M. (2024); https://BioRender.com/z65l923 (accessed on 6 November 2024).
Figure 2
Figure 2
The significance of kinase-independent activities of CDK4/6 kinases. Based on [14,15]. Created in BioRender. Sienczyk, M. (2024); https://BioRender.com/j69m843 (accessed on 6 November 2024).
Figure 3
Figure 3
The history and development of palbociclib based on Pfizer datasheets. Created in BioRender. Sienczyk, M. (2024); https://BioRender.com/o20f315 (accessed on 6 November 2024).
Figure 4
Figure 4
Structure of palbociclib (A) and its binding mode (B) to CDK6 (PDB ID: 5L2I). Magenta—palbociclib; cyan part of the CDK6 structure—N-lobe; cyan sticks—ATP binding site; green part of the CDK6 structure—C-lobe; hinge region—yellow sticks. Palbociclib regions responsible for interactions with the ribose pocket and the adenine pocket, based on Shan et al. [99]. Created in BioRender. Sienczyk, M. (2024); https://BioRender.com/b49h651 (accessed on 6 November 2024).
Figure 5
Figure 5
Palbociclib derivatives with antiproliferative potential [99,100,101,102]. Created in BioRender. Sienczyk, M. (2024); https://BioRender.com/y81q468 (accessed on 6 November 2024).
Figure 6
Figure 6
The principle of targeted protein degradation using CDK4/6-directed PROTACs [106]. Created in BioRender. Sienczyk, M. (2024); https://BioRender.com/o44i201 (accessed on 6 November 2024).
Figure 7
Figure 7
Examples of PROTAC compounds directed against CDK4/6 with various recruiters of E3 ligases [28,107,108,109,110,111]. Created in BioRender. Sienczyk, M. (2024); https://BioRender.com/q78b112 (accessed on 6 November 2024).
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