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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
The transcription of eukaryotic protein-encoding genes is controlled by ribonucleic acid polymerase II (RNAPII) in the elongation phase. Interplay between negative and positive elongation factors (referred to as N-TEF and P-TEF, respectively) regulates the elongation potential of RNAPII. P-TEFb is the first and only known component of P-TEF. The cyclin T-CDK9 complex (P-TEFb) phosphorylates and activates the carboxy-terminal domain (CTD) of RNAPII preferentially at Ser2 and most likely at Ser5 as well (6), leading to promotion of transcriptional elongation, events sensitive to 5,6-Dichloro-1-β-D-ribofuranosylbenzimidaloe (DRB), a well-known inhibitor of transcriptional elongation (6). In addition, CDK9 may act as a multifunctional kinase rather than solely as a CTD kinase (or transcriptional CDK) in cell differentiation, apoptosis, and cell cycle regulation pathways. For example, the cyclin T-CDK9 complex phosphorylates pRb (7). In addition, the initiation phase of transcription has been linked to CDK7 activation/initiation (8). An important implication of these findings is that in addition to the effects on cell cycle progression, disruption of CDK function can have profound effects on gene transcription.
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.
A patent review of selective CDK9 inhibitors in treating cancer
Published in Expert Opinion on Therapeutic Patents, 2023
Tizhi Wu, Xiaowei Wu, Yifan Xu, Rui Chen, Jubo Wang, Zhiyu Li, Jinlei Bian
It has been well documented that dysregulation of CDK9 signaling pathway is closely related to unlimited proliferation and differentiation of a variety of tumors. Moreover, inhibition of CDK9 effectively regulates the protein levels of oncogenic factors Mcl-1 and c-Myc proteins. Therefore, targeting CDK9 is considered to be a promising strategy for treating cancers, and the development of CDK9 inhibitors has gained increasing attention. However, the first generation of broad-spectrum CDK9 inhibitors may lead to unpredictable toxicities due to poor selectivity. Hence, the development of highly selective CDK9 inhibitors has attracted widespread attention. Several CDK9 inhibitors with high specificity have already entered clinical studies. In addition, the indications for clinical CDK9 inhibitors are gradually expanding from hematological tumors to solid tumors, including breast cancer and NSCLC. Notably, CDK9 inhibitors have displayed great potential to overcome drug resistance, including resistance in NSCLC. Furthermore, the author thinks that the combination of CDK9 inhibitor and targeted drugs for lung cancer is worthy of further study, which provides a new direction for the application of CDK9 inhibitors and may benefit lung cancer patients who develop resistance to the targeted therapeutic agents.
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
Similar effects of targeting CDK9 were also reported for TNBC. The correlation between elevated CDK9 expression and worse OS was observed based on the TCGA database, and TNBC cell lines with high CDK9 expression were more sensitive to atuveciclib, a small molecular that selectively targets the P-TEFb complex, in comparison to those with low CDK9 expression [92]. Along with significant PARP cleavage found in atuveciclib-treated TNBC cells, diminished protein levels of MYC and MCL1 dependent on RNAPII activity were reported by the Brisard group (Table 1) [92]. MYC and the anti-apoptotic factor MCL1, downstream targets of CDK9, are associated with the clinical consequences of TNBC patients [93,94]. Apart from anti-neoplastic effects on tumor cells, tumor-infiltrating BC stem cells (CSCs) were disrupted in TNBC tumors with high CDK9 expression following CDK9 inhibition (Table 1) [92]. Together, these observations suggest that CDK9i not only downregulate the downstream targets of CDK9 at transcriptional level and thereby promote tumor cells apoptosis but also influence CSCs. In fact, atuveciclib displayed anti-tumor effects against multiple neoplasms, including TNBC, in a phase I clinical trial [95] while other selective CDK9 inhibitors are still being research (Table 2). Furthermore, atuveciclib could potentially enhance the cytotoxic effects of conventional chemotherapeutic agents [92].
Keeping up with venetoclax for leukemic malignancies: key findings, optimal regimens, and clinical considerations
Published in Expert Review of Clinical Pharmacology, 2021
Maria Siddiqui, Marina Konopleva
Resistance mechanisms as identified above include MCL-1 and BCL-XL under the selective pressure of leukemic therapy. Emerging therapies are focused on MCL-1 inhibition with several agents currently under investigation. These include direct MCL-1 inhibitors like AMG-176 and MIK 665. Other agents focus on indirectly decreasing MCL-1 levels. For example, the mitogen-activated protein kinase (MAPK) pathway stabilizes MCL-1. Cobimetinib, an MEK inhibitor, downregulates MCL-1 by suppressing the MAPK pathway [133]. A decrease in p53, NOXA, and BAX can lead to an increase in MCL-1 and venetoclax resistance [129]. Murine double homolog 2 (MDM2) inhibitors have been identified to cause p53 activation and subsequent MCL-1 degradation [44]. Cyclin- dependent kinase 9 (CDK9) inhibitors interfere with transcription of MCL-1 resulting in downregulation [134]. Preclinical studies have also identified that combined inhibition of BCL-2 and MCL-1 aids in overcoming resistance to AML cell lines with prior exposure to venetoclax [135].