Cyclin dependent kinase (CDK) inhibitors as anticancer drugs

Sánchez-Martínez, Concepción; Gelbert, Lawrence M.; Lallena, Marı́a José; Dios, Alfonso De

doi:10.1016/j.bmcl.2015.05.100

Cited by 208 publications

(183 citation statements)

References 70 publications

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“…Therefore, the inhibition of CDKs in malignant cells provides a promising approach in the defense against cancer. Recently, many selective CDK inhibitors targeting specific CDKs were developed, which represent promising anti-cancer drugs due to their strong anti-proliferative efficacy combined with a relative low direct cytotoxicity [7–14]. Notably, palbociclib (IBRANCE ® ), a dual CDK4/6 inhibitor, recently received accelerated approval by the Food and Drug Administration (FDA) for clinical breast cancer treatment due to its potent and selective inhibitory effect on estrogen receptor (ER) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer [15–18].…”

Section: Introductionmentioning

confidence: 99%

The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer

et al. 2016

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Overexpression and/or hyperactivation of cyclin-dependent kinases (CDKs) are common features of most cancer types. CDKs have been shown to play important roles in tumor cell proliferation and growth by controlling cell cycle, transcription, and RNA splicing. CDK4/6 inhibitor palbociclib has been recently approved by the FDA for the treatment of breast cancer. CDK11 is a serine/threonine protein kinase in the CDK family and recent studies have shown that CDK11 also plays critical roles in cancer cell growth and proliferation. A variety of genetic and epigenetic events may cause universal overexpression of CDK11 in human cancers. Inhibition of CDK11 has been shown to lead to cancer cell death and apoptosis. Significant evidence has suggested that CDK11 may be a novel and promising therapeutic target for the treatment of cancers. This review will focus on the emerging roles of CDK11 in human cancers, and provide a proof-of-principle for continued efforts toward targeting CDK11 for effective cancer treatment.

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Section: Introductionmentioning

confidence: 99%

The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer

et al. 2016

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“…1; refs. 4,[7][8][9]. This approach has proven challenging because sufficient on-target potency, kinome selectivity (1), and appropriate CDK family selectivity must be incorporated in a single molecule.…”

Section: Introductionmentioning

confidence: 99%

“…Second-generation CDK-directed drugs were designed to be more potent and selective (dinaciclib, AT7519, R547, SNS-032, BMS-387032, AZD5438, AG-024322; refs. 7,8). Dinaciclib is reported to be a CDK1/2/ 5/9 inhibitor which was evaluated for treating breast cancer patients but toxicities hampered its utility (10).…”

Section: Introductionmentioning

confidence: 99%

Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance

Chen

Lee

et al. 2016

Molecular Cancer Therapeutics

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Therapeutically targeting aberrant intracellular kinase signaling is attractive from a biological perspective but drug development is often hindered by toxicities and inadequate efficacy. Predicting drug behaviors using cellular and animal models is confounded by redundant kinase activities, a lack of unique substrates, and cell-specific signaling networks. Cyclin-dependent kinase (CDK) drugs exemplify this phenomenon because they are reported to target common processes yet have distinct clinical activities. Tumor cell studies of ATP-competitive CDK drugs (dinaciclib, AG-024322, abemaciclib, palbociclib, ribociclib) indicate similar pharmacology while analyses in untransformed cells illuminates significant differences. To resolve this apparent disconnect, drug behaviors are described at the molecular level. Nonkinase binding studies and kinome interaction analysis (recombinant and endogenous kinases) reveal that proteins outside of the CDK family appear to have little role in dinaciclib/palbociclib/ribociclib pharmacology, may contribute for abemaciclib, and confounds AG-024322 analysis. CDK2 and CDK6 cocrystal structures with the drugs identify the molecular interactions responsible for potency and kinase selectivity. Efficient drug binding to the unique hinge architecture of CDKs enables selectivity toward most of the human kinome. Selectivity between CDK family members is achieved through interactions with nonconserved elements of the ATPbinding pocket. Integrating clinical drug exposures into the analysis predicts that both palbociclib and ribociclib are CDK4/6 inhibitors, abemaciclib inhibits CDK4/6/9, and dinaciclib is a broad-spectrum CDK inhibitor (CDK2/3/4/6/9). Understanding the molecular components of potency and selectivity also facilitates rational design of future generations of kinase-directed drugs.

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“…Some of these problems have been solved, and a chimeric peptide acting as a surrogate of the endogenous p16 INK4A inhibitor linked to a cell-penetrating peptide (MM-D37K, Metamax) inhibits phosphorylation of the retinoblastoma protein and leads to G1 cell cycle arrest. The MM-D37K peptide also inhibits tumor growth in lung and colon xenograft models, and the compound is now enrolled in a Phase I/IIa clinical trial [91,97,98]. Future research may also aim to develop small molecules to interfere with protein/protein interactions ( Figure 3B), a strategy that has already been successfully used to interrupt the interaction of p53 (tumor protein P53/TP53) with MDM2 (MDM2 proto-oncogene, E3 ubiquitin protein ligase) [99].…”

Section: Cdk Inhibitors For the Treatment Of Inflammatory Diseasesmentioning

confidence: 98%

“…The interaction of CDK/cyclin complexes with different interacting proteins enables the development of molecules blocking these protein/protein interactions, as schematically shown in Figure 3B. Peptidomimetic molecules have been designed to mimic endogenous substrates to interfere with the binding between CDKs and their interaction partners such as cyclins [90][91][92]. Another approach relies on the principle to deliver peptides mimicking the activity of endogenous CDK inhibitors such as p16 INK4A , p21 CIP1 , and p27 KIP1 [93][94][95][96].…”

Section: Cdk Inhibitors For the Treatment Of Inflammatory Diseasesmentioning

confidence: 99%

Cyclin-Dependent Kinases as Coregulators of Inflammatory Gene Expression

Schmitz

2016

Trends in Pharmacological Sciences

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Cyclin dependent kinase (CDK) inhibitors as anticancer drugs

Cited by 208 publications

References 70 publications

The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer

The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer

Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance

Cyclin-Dependent Kinases as Coregulators of Inflammatory Gene Expression

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