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Personalized Medicine in Lung Cancer
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Daniela Morales-Espinosa, Silvia Garcá-Román, Rafael Rosell
Many drugs target CDKs as these are deregulated in cancer cells. Their inhibitors compete with ATP for the enzyme active site. Therefore, CDK inhibition results in RNPII hypophosphorylation.51 The most commonly targeted CDKs are CDK7, CDK8 and CDK9. CDK7 is a component of basal transcription factor TFIIH that phosphorylates Serine 5 and 7 in the C-terminal domain (CTD) of the RNPII, which is important for promoter escape and recruitment of mRNA processing machinery during transcription.52 CDK9 is also a component of P-TEFb, which, similar to CDK7, phosphorylates CTD of RNPII at serine 2 for transcription elongation.53, 54 The same activity is observed with the CDK8 kinase, which phosphorylates CTD of RNPII, resulting in inhibition of transcription initiation complex.
Molecular Targets Other than BCR-ABL: How to Incorporate them into the CML Therapy?
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
V. Melo Junia, J. Barnes David
Multiple cyclin-dependent kinases (CDKs) including, CDK1, CDK2, CDK4/6, and CDK7, are targeted by the semi-synthetic flavone, flavopiridol (L86–8275, HMR 1275; National Cancer Institute, Bethesda, Maryland, U.S.A.) (49). Co-treatment with imatinib and flavopiridol led to increased mitochondrial damage, activation of caspases and apoptosis in CML cell lines but not in leukemia cell lines that did not express Bcr-Abl (49). In addition, this drug combination effectively induced apoptosis in an imatinib-resistant CML cell line that overexpressed Bcr-Abl (49). As mentioned earlier, synergistic induction of apoptosis has been reported for the combination of flavopiridol and the proteasome inhibitor, bortezomib, in imatinib-sensitive and resistant CML cell lines (48). Unlike some of the other therapeutic agents previously discussed, flavopiridol has only recently been recognized as a potential treatment for CML. A phase I trial to identify appropriate dose combinations of imatinib and flavopiridol was conducted in 2005 in 21 patients with Bcr-Abl-positive hematologic malignancies (50). This combination was found to be tolerable and was responsible for four objective responses, including two complete hematologic remissions (50). Further clinical trials will be required to establish the efficacy of drug combinations containing flavopiridol.
CDK Inhibitors in Leukemia and Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Of the large number of CDK complexes identified, CDKs 1, 2, 4, and 6 and cyclins A (A1 and A2), B (B1 and B2), D (D1, D2, and D3), and E (E1 and E2) are directly involved in the cell cycle machinery. Generally, cyclins D-CDK4 and D-CDK6 phosphorylate or inactivate the retinoblastoma protein (pRb, a major member of the “pocket protein” family) and release transcriptional factors E2Fs (activated) from an inactive pRb-E2F complex. E2F binds to its heterodimeric partner DP-1 and induces the expression of genes that is responsible for S-phase entry and progression, including cyclin E. In addition, cyclin E-CDK2 also facilitates G1→S transition by further phosphorylating pRb, complete activation of which requires phosphorylation by both cyclin D-CDK4/6 (hypophosphorylation) and cyclin E-CDK2 (hyperphosphorylation) (4). Cyclin D-CDK4, but not cyclin E-CDK2, also phosphorylates p130 and p107 (additional members of the “pocket protein” family), which may interact with certain E2Fs (e.g., E2F1 and 4) and mimic the function of pRb in RB null tumor cells. In the S phase, cyclin A-CDK2 phosphorylates various substrates, which allows DNA replication and also inactivates G1 transcriptional factors (i.e., E2Fs). Cyclin A-CDK1/CDC2 and cyclin B-CDK1/CDC2 govern G2→M transition. The cyclin B-CDK1 complex also regulates the transition of cells into anaphase and through mitosis. In addition, certain CDK complexes, e.g., cyclin A-CDK2 in the S phase and cyclin B1-CDK1 in the G2/M phase, are associated with the DNA replication competent (RC) complex, which may be directly involved in regulation of DNA replication (5). Lastly, cyclin H-CDK7 (also known as CAK) activates CDKs 1, 2, 4, and 6 via phosphorylation at specific threonine residues, events required for full activation of these CDKs.
A patent review of cyclin-dependent kinase 7 (CDK7) inhibitors (2018-2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Markéta Kovalová, Joseph Peter Baraka, Václav Mik, Radek Jorda, Lei Luo, Hao Shao, Vladimír Kryštof
The interest in pursuing CDK7 as a therapeutic target has been ongoing for at least one decade, and significant progress has been achieved in the past few years. The field of CDK7 inhibitors is continuously growing, spanning diverse chemical classes and promising kinase selectivity. In addition, the available compounds possess different mechanisms of inhibition, including conventional competition, irreversible binding and specific induction of CDK7 degradation by heterobifunctional compounds. The new compounds disclosed in 58 patent applications published during the reviewed period, i.e. from 2018 to 2022, span over 15 chemotypes. We classified and summarized the chemical structures and their biochemical and biological properties, providing researchers with a comprehensive update of the field, including exciting clinical candidates.
Recent progress in development of cyclin-dependent kinase 7 inhibitors for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2021
Hanzhi Liang, Jintong Du, Reham M. Elhassan, Xuben Hou, Hao Fang
CDK7 is widely involved in regulating the cell cycle and transcription. The inhibition of CDK7 activity may reduce gene expression at a global level and affect other normal physiological functions. It has been found that THZ1 could inhibit the phosphorylation of the CTD residues of RNA Pol II in neurons and reduce the expression of IEGs (Npas4, Egrl, c-Fos, Nr4al, and Arc), which were related to learning and memory [22]. CDK7 was essential for the expression of immediate early genes in activity-dependent neurons, long-term synaptic plasticity, and the formation of long-term memory [22,131]. Recent data suggest that the regulation of metabolism and energy is also modulated by CDK7 [23,132]. In cardiac-specific knockout mice, the CDK7 complex was related to the gene expression of myocardial mitochondrial metabolism, which was of great significance in preventing heart failure [133]. At the same time, it was have found that in CRC cells, treatment of THZ1 can increase the expression of Snail, reduce the expression of protein kinase D1, and improve the ability of CRC cells to undergo epithelial-mesenchymal transition and metastasis to the liver [134].
Cyclin-dependent kinase inhibition and its intersection with immunotherapy in breast cancer: more than CDK4/6 inhibition
Published in Expert Opinion on Investigational Drugs, 2022
Xianan Guo, Huihui Chen, Yunxiang Zhou, Lu Shen, Shijie Wu, Yiding Chen
There are several CDK7 inhibitors under study, both preclinically and clinically: 1) non-covalent inhibitors such as LDC4297, QS1189, BS-181, and ICEC0942; and 2) covalent inhibitors such as THZ1, THZ2, and YKL-5-124 [32].