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  • br CDK Inhibitors for the Treatment

    2019-12-04


    CDK Inhibitors for the Treatment of inflammatory Diseases Several CDKs have been implicated as regulators of inflammatory gene expression. It will thus be very important to determine the relative contributions of the various CDKs and their kinase function on a systematic basis. This work will be the prerequisite for target identification and drug development. CDK4, CDK6, and CDK7/9 are well-defined targets for inhibitors used for the treatment of cancer 82, 83, 84. From the 11 inhibitors currently undergoing clinical evaluation, palbociclib, LY2835219 (abemaciclib), and LEE-011 (ribociclib) have advanced to Phase III clinical trials in breast and lung cancer [85] (www.clinicaltrials.gov). These three drugs (Figure 3A) function as ATP competitive inhibitors. Specific cancers such as advanced breast cancer show significantly improved progression-free survival when the oral small-molecule inhibitor CDK 4/6 inhibitor palbociclib is used as an adjuvant 86, 87, 88. Palbociclib (Ibrance®) is the first CDK inhibitor to reach the clinic because it was recently approved in the USA for first-line treatment of advanced breast cancer in combination with the aromatase inhibitor letrozole [85]. Palbociclib also inhibits the IL1-inducible expression of the endogenous IL8 gene in tissue culture h89 [36], and it will be important to determine its anti-inflammatory activity in vivo. In addition, a variety of experimentally used CDK inhibitors such as BAI, Honokiol, or CR8 were found to inhibit NF-κB and to display anti-inflammatory activities in cell culture models [89]. In addition, CDK inhibitors which are currently in clinical trials (e.g., the broad-spectrum CDK inhibitor roscovitine) inhibit NF-κB-driven inflammation and contribute to the resolution of inflammation by promoting inflammatory cell apoptosis [29]. As discussed above, the association of CDK6 with proinflammatory transcription factors does not depend on its kinase activity. This might be due to the function of CDK6 as a scaffolding protein mediating protein/protein interactions. CDK induction relies on the association with their partner cyclins, and full activation of some CDKs such as CDK4 depends additionally on substrate binding [2]. 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 p16INK4A, p21CIP1, and p27KIP193, 94, 95, 96. These different approaches are schematically summarized in Figure 3B. While peptidomimetics can interrupt protein/protein interactions with high specificity, the first generation of these molecules suffered from limited cell penetration properties and stability. Some of these problems have been solved, and a chimeric peptide acting as a surrogate of the endogenous p16INK4A 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].
    Concluding Remarks Initially identified as a molecular machinery driving cells through the cell cycle, it is now clear that the CDK/cyclin system fulfils many additional biological functions. CDK research is a mature field that was even covered with the Nobel Prize in 2001, but it took until this year before the CDK4/6 inhibitor palbociclib was approved by the USA FDA for the treatment of breast cancer in post-menopausal women. While a proinflammatory role of CDKs emerged some time ago, the molecular mechanisms employed by proinflammatory CDKs are only now beginning to be unraveled. Many open questions remain (see Outstanding Questions for an incomplete list). The well-established CDK/cyclin field offers a large portfolio of tools that range from small-molecule inhibitors to sophisticated mouse models. These instruments can now readily be used to identify the acute or chronic inflammatory disease(s) that could be treated with CDK inhibitors. Inhibition of CDK activity could also be an important adjuvant therapy for those tumors that rely on a proinflammatory microenvironment (Figure 3C). This is also the case for breast cancer, and it remains to be seen if inhibition of inflammation is one of the mechanisms of action of palbociclib in this disease [100]. Further, CDK inhibition may also be a promising avenue for the treatment of non-cancerous chronic inflammatory conditions.