Herein, we discuss more than 50 cyclin-dependent kinase (CDK) inhibitors that have been approved or have undergone clinical trials and their therapeutic application in multiple cancers. This review discusses the design strategies, structure-activity relationships, and efficacy performances of these selective or nonselective CDK inhibitors. The theoretical basis of early broad-spectrum CDK inhibitors is similar to the scope of chemotherapy, but because their toxicity is greater than the benefit, there is no clinical therapeutic window. The notion that selective CDK inhibitors have a safer therapeutic potential than pan-CDK inhibitors has been widely recognized during the research process. Four CDK4/6 inhibitors have been approved for the treatment of breast cancer or for prophylactic administration during chemotherapy to protect bone marrow and immune system function. Furthermore, the emerging strategies in the field of CDK inhibitors are summarized briefly, and CDKs continue to be widely pursued as emerging anticancer drug targets for drug discovery.

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy.

Cdk7, the CDK-activating kinase and transcription factor IIH component, is a target of inhibitors that kill cancer cells by exploiting tumor-specific transcriptional dependencies. However, whereas selective inhibition of analog-sensitive (AS) Cdk7 in colon cancer-derived cells arrests division and disrupts transcription, it does not by itself trigger apoptosis efficiently. Here, we show that p53 activation by 5-fluorouracil or nutlin-3 synergizes with a reversible Cdk7as inhibitor to induce cell death. Synthetic lethality was recapitulated with covalent inhibitors of wild-type Cdk7, THZ1, or the more selective YKL-1-116. The effects were allele specific; a CDK7as mutation conferred both sensitivity to bulky adenine analogs and resistance to covalent inhibitors. Non-transformed colon epithelial cells were resistant to these combinations, as were cancer-derived cells with p53-inactivating mutations. Apoptosis was dependent on death receptor DR5, a p53 transcriptional target whose expression was refractory to Cdk7 inhibition. Therefore, p53 activation induces transcriptional dependency to sensitize cancer cells to Cdk7 inhibition.

Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors

Background Gastric cancer (GC) is a major cancer-related mortality disease. Gambogic acid (GA) has been investigated to inhibit cancer progression. In the present study, the molecular mechanism of GA in regulating GC progression was studied. Methods The expression levels of circular RNA ASAP2 (circ_ASAP2), miR-33a-5p and cyclin-dependent kinases 7 (CDK7) were detected by quantitative real-time polymerase reaction (qRT-PCR). CDK7 protein level was evaluated by Western blot. Cell colony formation assay, 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, transwell assay and flow cytometry analysis were employed to reveal the functional effects among circ_ASAP2, miR-33a-5p and CDK7 on GA-induced GC progression. Mechanistically, the binding relationship between miR-33a-5p and circ_ASAP2 or CDK7 was predicted with starBase v3.0 online database and verified by dual-luciferase reporter assay. In vivo tumor formation assay was used to explain the impacts of GA treatment on GC growth in vivo. Results Circ_ASAP2 and CDK7 expression were downregulated in GA-induced GC cells compared with GC cells. MiR-33a-5p expression was upregulated in GA-induced GC cells relative to GC cells. The protein expression level of CDK7 was lower in GA-induced GC cells than that in GC cells. Further, circ_ASAP2 overexpression decreased GA-induced inhibition effects on cell proliferation, migration and invasion and GA-induced promotion effect on cell apoptosis in both AGS and HGC-27 cells, whereas this phenomenon was reversed by miR-33a-5p. In addition, circ_ASAP2 functioned as a sponge of miR-33a-5p and miR-33a-5p was associated with CDK7. Furthermore, GA treatment inhibited GC growth in vivo. Conclusion Circ_ASAP2 overexpression promoted cell proliferation, migration and invasion, whereas inhibited cell apoptosis by upregulating CDK7 expression through binding to miR-33a-5p in GA-induced GC cells. This study provided a theoretical basis in GC treatment with GA.

/pdf/gambogic-acid-inhibits-the-progression-of-gastric-cancer-via-3fzysyjs1p.pdf

Gambogic Acid Inhibits the Progression of Gastric Cancer via circRNA_ASAP2/miR-33a-5p/CDK7 Axis.

Cyclin-dependent kinases (CDKs) are pivotal mediators and effectors of the DNA damage response (DDR) that regulate both the pathway components and proteins involved in repair processes. Synthetic lethality (SL) describes a situation in which two genes are linked in such a way that the lack of functioning of just one maintains cell viability, while depletion of both triggers cell death. Synthetic lethal interactions involving CDKs are now emerging, and this can be used to selectively target tumor cells with DNA repair defects. In this review, SL interactions of CDKs with protooncogene products MYC, poly (ADP-ribose) polymerase (PARP-1), and cellular tumor antigen p53 (TP53) are discussed. The individual roles of each of the SL partners in DDR are described.

/pdf/cyclin-dependent-kinase-synthetic-lethality-partners-in-dna-3ud2atsz.pdf

Cyclin-Dependent Kinase Synthetic Lethality Partners in DNA Damage Response

Selective covalent CDK7 inhibitor THZ1 is a promising potential anti-tumor drug in many kinds of cancers. Epithelial-mesenchymal Transition (EMT) is highly related to cancer initiation, development, invasion and metastasis and other pathogenesis processes. We treated cancer cell line Hela229 and three retinoblastoma cell lines so-RB50, WERI-Rb-1, Y79 with gradient concentration of THZ1, and found that THZ1 could inhibit cell viability and EMT, suggesting that THZ1 may be a promising drug for human cervical cancer and retinoblastoma treatment. Our results verified the role of THZ1 in EMT for the first time, however, the mechanism needs further study. Here we report that THZ1 suppresses the TGFβ2 induced EMT in human SRA01/04 lens epithelial cells (LECs), rabbit primary lens epithelial cells, and whole rat lens culture semi-in vivo model. RNA-sequencing and KEGG analysis revealed that the THZ1 inhibits EMT by down-regulating phosphorylate Smad2 and Notch signaling pathway. On the other hand, we found that THZ1 could strongly inhibit LECs proliferation through G2/M phase arrest as well as attenuating of MAPK, PI3K/AKT signaling pathway. Our results uncovered the function and underlying mechanism of THZ1 in regulation of EMT, which provides a new perspective of the anti-tumor effect by THZ1 and may offer a novel treatment for PCO.

/pdf/anti-tumor-drug-thz1-suppresses-tgfb2-mediated-emt-in-lens-4k1z2goj44.pdf

Anti-tumor Drug THZ1 Suppresses TGFβ2-mediated EMT in Lens Epithelial Cells via Notch and TGFβ/Smad Signaling Pathway.

Cyclin-dependent kinase 7 inhibitor THZ1 in cancer therapy.

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Cyclin-dependent kinase 7 inhibitor THZ1 in cancer therapy.