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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Although the various stages of interphase are not usually distinguishable from a morphological perspective, each phase of the cell cycle has a set of distinct biochemical processes that prepare the cell for division. Many of the relevant genes were first identified by studying yeast, especially Saccharomyces cerevisiae. The CDK4/6 and CDK2 kinases are required for progression through G1 of the cell cycle and entry into S-phase, and control of these kinases occurs at multiple levels. The first level involves accumulation of the cyclin, the second is assembly into a cyclin-CDK complex, and the third is specific phosphorylation and dephosphorylation events. Additional regulation of G1 CDK activity is mediated by association with inhibitory proteins, the CKIs, that can physically block activation or block substrate/ATP access. The known CKIs are grouped into two gene families, Ink4 and Cip/Kip, according to their structural similarities. The D-type cyclins and their corresponding partner kinases CDK4 and CDK6 act as central integrators of extracellular signals and operate during the G1 phase of the cell cycle by phosphorylating the tumor-suppressor protein pRb, thus contributing to its inactivation. Mutations that can influence the function of cyclins CDK4 and CDK6, their regulating proteins, or pRB, can be found in most human tumors. Furthermore, cyclin D1 expression can be up-regulated by the Ras signaling pathway, which is itself up-regulated in many cancer cell types.
Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Alastair G. Stewart, Paul R. Tomlinson, Leslie Schachte
Cyclins have no intrinsic protein kinase activity, but function as regulatory elements of protein kinases known as Cdks.154 Cyclin D associates with Cdk4 or Cdk6.160–162 Cyclin E associates with Cdk2.163,164
Cutaneous Malignant Melanoma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The CDK4 (cyclin dependent kinase 4) gene on chromosome 12q14.1 spans 8.2 kb and encodes a 303 aa, 33.7 kDa protein (CDK4) belonging to the Ser/Thr protein kinase family. As the catalytic subunit of the protein kinase complex, CDK4 along with its partner CDK6 is involved in the phosphorylation of Rb, and thus plays an important role in cell cycle G1 phase progression. CDK4 activity is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16. Alterations in CDK4 are implicated in a small proportion of familial malignant melanoma.
Binding selectivity-dependent molecular mechanism of inhibitors towards CDK2 and CDK6 investigated by multiple short molecular dynamics and free energy landscapes
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Lifei Wang, Dan Lu, Yan Wang, Xiaoyan Xu, Peihua Zhong, Zhiyong Yang
Enhanced resistance to apoptosis and loss of cell-cycle regulation are principal hallmarks of cancers1. Cyclin-dependent kinases (CDKs), a family of 13 members containing CDK1-CDK132, are proline-directed serine-threonine kinases which related to an activating cyclin regulatory subunit3. CDK2 is an important macromolecule in cell cycle regulation, with taking part in inactivation and phosphorylation of the retinoblastoma protein (RB) tumour suppressor family and regulating both G1/S and G2/M progressions4,5. Furthermore, CDK2 strengthens DNA replication and plays a critical role in cell cycle in the DNA damage response6. CDK6 is regarded as a typical cell cycle kinase that boosts arrest of sensitive tumour cells in the G1 phase of the cell cycle. CDK6 takes part in the process of cancer development by using the kinase-dependent or non-kinase-dependent function7. Based on importance in promoting cancer initiation as well as progression, CDK2 and CDK6 have drawn intense interest as promising therapeutic targets for cancer.
Combined endocrine and targeted therapy in luminal breast cancer
Published in Expert Review of Anticancer Therapy, 2021
Marcelle Goldner, Natasha Pandolfi, Debora Maciel, Julianne Lima, Solange Sanches, Noam Pondé
The class of CDK4/6i has three oral drugs currently approved for treating HR+ HER2-advanced breast cancer named palbociclib, ribociclib, and abemaciclib, which have specific pharmacological properties suggesting that there might have a different spectrum of sensitivity to cyclins’ inhibition, which translates into a drug-specific toxicity profile [80,81]. For instance; palbociclib and ribociclib have comparable specificity to inhibit CDK4 and CDK6, while abemaciclib has shown to be more selective to CDK4 than CDK6, also with activity against CDK978. As a result, hematological adverse events such as neutropenia and anemia are more frequently reported among patients treated with palbociclib and ribociclib, QTc prolongation had been reported in patients receiving ribociclib [64,65], while diarrhea is more commonly found among patients treated with abemaciclib. Risks related to secondary events should not be overlooked and must be individualized.
Abemaciclib, a third CDK 4/6 inhibitor for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer
Published in Expert Review of Anticancer Therapy, 2021
Georges El Hachem, Andrea Gombos, Ahmad Awada
A major hallmark of cancer cells survival is to evade extracellular and intracellular signals that are blocking proliferation [8,9]. The retinoblastoma (RB)-associated protein (tumor suppressor) is a major negative regulator of cell cycle progression. It is involved in determining whether a cell will proceed through the cycle of growth and division or enter a quiescent phase [10]. Regularly, the mammalian cell must pass the restriction point, called ‘’R,” a checkpoint essential to complete the cell cycle during the G1 phase [11]. Regulation of one or more proteins involved in this checkpoint is lost in many cancers. The activation of CDK4 and CDK6 by D-cyclins results in phosphorylation of the retinoblastoma-associated protein, thus allowing the cell to pass the “R” point and commit to division. When it is hyperphosphorylated, RB suppressive effect is inactivated leading to release of E2F family of transcription factors necessary for the progression of the cell cycle through the G1 to the S checkpoints [11]. Thus, CDK4 and 6 are involved in the promotion of cell cycle progression and their up-regulation is a major event for the proliferation and progression of breast cancer cells [11–13]. By inhibiting the CDK4/6, the cyclin D-CDK4/6 complex would not be able to phosphorylate RB. This prevents the cell from passing ''R'', and consequently from proceeding through the cell cycle. Figure 2 illustrates the mechanism of action of the CDK 4/6 inhibitors.