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Characterization of the novel CDK7 inhibitor QS1189. (a) Selectivity and target profile of 1 μM QS1189 against approximately 410 kinases in a multikinase inhibition assay in vitro. Shown are kinases whose activity was inhibited by >80% at the dose tested. (b) MCL cells were treated with ibrutinib, venetoclax, and QS1189 for 72 h. Cell viability was evaluated using the MTT assay and IC 50 values were calculated. (c) MCL ells were treated with the indicated dose of QS1189 for 6 h. The indicated protein levels were analysed by immunoblotting.
Source publication
Mantle cell lymphoma (MCL) is typically an aggressive and rare form of non-Hodgkin lymphoma (NHL) with a poor prognosis despite recent advances in immunochemotherapy and targeted therapeutics against NHL. New therapeutic agents are needed for MCL. In this study, we generated a potent inhibitor of cyclin-dependent kinase 7 (CDK7), designated QS1189,...
Contexts in source publication
Context 1
... of novel CDK7 inhibitor. We generated a pharmaceutically active pyrazolo-triazine derivative as a selective inhibitor of CDK7. This compound was designated as QS1189. QS1189 potently inhibited CDK7 activity among a panel of 410 kinases in a multikinase inhibition assay in vitro (Fig. 1a and Supplemental Table S1). Although QS1189 showed similar inhibition to other CDKs including CDK16/CycY, CDK5/p35NCK, CDK2/CycE1, and CDK5/p25NCK, QS1189 inhibited CDK7 activity in vitro with an IC 50 of 15 nM and showed IC 50 values that were 10-600-fold higher than those of other CDKs (Supplemental Table ...
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... activity of QS1189 compared to those of conventional drugs such as ibrutinib and venetoclax in MCL cells. Most MCL cells showed resistance to ibrutinib and venetoclax, although venetoclax showed growth inhibition with an IC 50 value in the nanomolar range (IC 50 value of 275.4 ± 62.9 and 50, 2.5 ± 0.4 nM for Mino and Maver-1 cells, respectively; Fig. 1b). However, QS1189 inhibited the growth of MCL cells with IC 50 values between 50 and 250 nM. Thus, QS1189 may be a more potent drug than other targeted agents for treating ...
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... initiation and RNAPII procession [29][30][31] . To evaluate the dose-dependent inhibition of CDK7 substrates by QS1189, we performed immunoblotting following treatment with QS1189. QS1189 treatment completely inhibited the phosphorylation of CDK7 substrate RNAPII CTD at Ser-2 and Ser-5 and slightly reduced RNAPII p-Ser7 CTD phosphorylation (Fig. 1c). Interestingly, QS1189 treatment led to reduced RNAPII expression. These results were also observed after 24 h of QS1189 treatment (Supplemental Fig. ...
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... following treatment with QS1189. QS1189 treatment completely inhibited the phosphorylation of CDK7 substrate RNAPII CTD at Ser-2 and Ser-5 and slightly reduced RNAPII p-Ser7 CTD phosphorylation (Fig. 1c). Interestingly, QS1189 treatment led to reduced RNAPII expression. These results were also observed after 24 h of QS1189 treatment (Supplemental Fig. ...
Citations
... Seliciclib (roscovitine), another CDK1, 2, 5, 7, and 9 inhibitor, was assessed in clinical trials for various tumor types; however, this also exhibited limited clinical activity [18,19]. Recently, various CDK7-specific inhibitors have been developed, such as BS-181 [20], ICEC0942 (CT7001; samuraciclib) [21][22][23], LY3405105 [24], LDC4297 [25], SY-1365 [26] (phase 1), THZ1 (SY-079) [27], THZ2 [28], YKL-5-124 [29], QS1189 [30], and SY-5609 [31]. Among them, SY-5609, THZ1, and THZ2 were tested preclinically against TNBC [28,31]. ...
Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.
... Notably, increased CDK7 expression correlates with a dismal prognosis [31]. Targeting CDK7 has revealed pronounced effects on cancer cell proliferation, migration, invasion, stemness, and drug resistance across malignancies such as breast cancer [32], lung cancer [33], hepatocellular carcinoma [34], thyroid cancer [35], glioblastoma [36], gastric cancer [37], pancreatic cancer [38], gallbladder cancer [39], colorectal cancer [40], osteosarcoma [41], lymphomas [42], leukemia [43], among others. In recent years, a range of specific small molecular inhibitors targeting CDK7 has been synthesized and classified, as detailed in Table 1. ...
... In recent years, a range of specific small molecular inhibitors targeting CDK7 has been synthesized and classified, as detailed in Table 1. The set encompasses reversible ATPbinding site inhibitors such as BS-181 [44], CT7001 [45], LDC4297 [46], QS1189 [42], SY-5609 [47]. Additionally, the development of ATP-competitive covalent inhibitors has further expanded this field, with notable examples including THZ1 [48], THZ2 [49], SY-1365 [50], YKL-5-124 [51], and YKL-1-116 [52]. ...
... --Mantle cell lymphoma [42] No studies entered clinical studies yet THZ1 ...
Cyclin-dependent kinase 7 (CDK7) serves as a pivotal regulator in orchestrating cellular cycle dynamics and gene transcriptional activity. Elevated expression levels of CDK7 have been ubiquitously documented across a spectrum of malignancies and have been concomitantly correlated with adverse clinical outcomes. This review delineates the biological roles of CDK7 and explicates the molecular pathways through which CDK7 exacerbates the oncogenic progression of breast cancer. Furthermore, we synthesize the extant literature to provide a comprehensive overview of the advancement of CDK7-specific small-molecule inhibitors, encapsulating both preclinical and clinical findings in breast cancer contexts. The accumulated evidence substantiates the conceptualization of CDK7 as a propitious therapeutic target in breast cancer management.
... Due to its essential role in cell cycle progression, inhibition of CDK7 causes cell cycle arrest (Ali et al., 2009;Chipumuro et al., 2014;Kelso et al., 2014;Choi et al., 2019;Olson et al., 2019). The extent and timing of cell cycle arrest vary among different cancer types: LDC4297 causes G1 arrest in A549 lung cancer cells, but in HCT116 colon cancer cells only causes G2/M delay after extended incubation (Kelso et al., 2014). ...
Enhancers are essential cis-acting regulatory elements that determine cell identity and tumor progression. Enhancer function is dependent on the physical interaction between the enhancer and its target promoter inside its local chromatin environment. Enhancer reprogramming is an important mechanism in cancer pathogenesis and can be driven by both cis and trans factors. Super enhancers are acquired at oncogenes in numerous cancer types and represent potential targets for cancer treatment. BET and CDK inhibitors act through mechanisms of enhancer function and have shown promising results in therapy for various types of cancer. Genome editing is another way to reprogram enhancers in cancer treatment. The relationship between enhancers and cancer has been revised by several authors in the past few years, which mainly focuses on the mechanisms by which enhancers can impact cancer. Here, we emphasize SE's role in cancer pathogenesis and the new therapies involving epigenetic regulators (BETi and CDKi). We suggest that understanding mechanisms of activity would aid clinical success for these anti-cancer agents.
... SNS-032, which inhibits CDK2, 7, and 9, has been evaluated for advanced solid tumors; however, the drug has not progressed further than phase I [16,17]. Recently, various CDK7-speci c inhibitors have been developed, such as BS-181 [18], ICEC0942 (CT7001; samuraciclib) [19][20][21], LY3405105 [22], LDC4297 [23], SY-1365 [24] (phase 1), THZ1 (SY-079) [25], THZ2 [6], YKL-5-124 [26], QS1189 [27], and SY-5609 [28]. Among them, SY-5609, THZ1, and THZ2 were tested preclinically against TNBC [6, 28]. ...
Background
Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancer types, indicating poor survival prognosis with more aggressive biology of rapidly progressive growth, metastasis to the lung, and short response duration to available therapies. TNBC is characterized by the negative expression of three hormone receptors. Therefore, compared to other breast cancers, TNBC is difficult to treat using hormone inhibitors and is resistant to chemotherapy. Additionally, the lack of effective targets limits the development of therapeutics. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed the following experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC.
Methods
Colony-forming, cell counting kit-8 (CCK-8), wound healing, trans-well assays, and western blotting were performed in vitro. An experimental metastasis model was developed via intravenous injection of MDA-MB-231-Luc cells in vivo, and tumor growth was monitored using an In Vivo Imaging System (IVIS) spectrum.
Results
The result showed that IB reduced the viability of various TNBC cell lines in a dose-dependent manner. Pretreatment with z-VAD effectively blocked IB-induced cell death and cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in TNBC cells. A reduction in the migration and invasion abilities of TNBC cell lines was observed following IB treatment in migration and invasion assays. We determined the expression levels of metastasis-related markers using western blotting and found that the expression of matrix metalloproteinase-9 (MMP-9) decreased in an IB dose-dependent manner. In addition, IB-induced inhibition of migration and invasion was blocked in MMP9-overexpressing MDA-MB-231-Luc cells. Results of in vivo experiments using the metastasis model showed that metastasis of MDA-MB-231-Luc cells to the lung was inhibited by IB.
Conclusions
Collectively, these results showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.
... CDK7 has been intensively pursued as anticancer drug target due to its dysregulated cell cycle control and transcription in cancer cells [2]. The overexpression of CDK7 has been observed in different cancer types, such as mantle cell lymphoma [7], breast cancer [8], multiple myeloma [9], colorectal cancer [10], gastric cancer [11], ovarian cancer [12], oral squamous cell carcinoma [13], glioblastoma [14], and hepatocellular carcinoma [15], and is correlated with tumor aggressiveness and a poor prognosis. CDK7 has also been found to directly phosphorylate or regulate the expression of oncogenic transcription factors, such as c-Myc [16], androgen receptor [17] and estrogen receptor [18]. ...
... QS1189 is a pyrazolo-triazine-based inhibitor discovered by Qurient, the originator of clinical candidate Q901. QS1189 inhibits CDK7 with an IC 50 of 15 nM, but it also shows similar inhibition of other CDKs, including CDK16, CDK2 and CDK5 [7]. QS1189 inhibited the growth of mantle cell lymphoma (MCL) cells with IC 50 values between 50 and 250 nM. ...
Introduction:
Cyclin-dependent kinase 7 (CDK7) is a member of the CDK family of serine/threonine protein kinases and participates in the regulation of the cell cycle and mRNA transcription. CDK7 is emerging as a possible drug target in oncology and six exciting drug candidates have already undergone early evaluation in clinical trials.
Areas covered:
This review examines CDK7 inhibitors as anticancer drugs reported in patents published in the online databases of the World Intellectual Property Organization and European Patent Office in the 2018-2022 period. This review provides an overview of available inhibitors, including their chemical structures, biochemical profile and stage of development.
Expert opinion:
Small-molecule CDK7 inhibitors represent attractive pharmacological modalities for the treatment of various cancer types. Highly potent and selective inhibitors have been discovered and many of them show promising results in several of preclinical cancer models. Developed compounds act on the kinase by various mechanisms, including traditional ATP competition, irreversible binding to tractable cysteine 312 outside the active site of CDK7, and induced protein degradation by proteolysis targeting chimeras. Ongoing preclinical research and clinical trials should reveal which strategy will provide the highest benefits.
... Recently, other CDK7 inhibitors have been introduced, some of which have already entered clinical trials, namely, LY3405105, Q901 and XL102. Nevertheless, limited information about their mode of action, kinase selectivity or structure has been disclosed [19][20][21][22][23]. ...
Targeting cyclin-dependent kinase 7 (CDK7) provides an interesting therapeutic option in cancer therapy because this kinase participates in regulating the cell cycle and transcription. Here, we describe a new trisubstituted pyrazolo[4,3-d]pyrimidine derivative, LGR6768, that inhibits CDK7 in the nanomolar range and displays favourable selectivity across the CDK family. We determined the structure of fully active CDK2/cyclin A2 in complex with LGR6768 at 2.6 Å resolution using X-ray crystallography, revealing conserved interactions within the active site. Structural analysis and comparison with LGR6768 docked to CDK7 provides an explanation of the observed biochemical selectivity, which is linked to a conformational difference in the biphenyl moiety. In cellular experiments, LGR6768 affected regulation of the cell cycle and transcription by inhibiting the phosphorylation of cell cycle CDKs and the carboxy-terminal domain of RNA polymerase II, respectively. LGR6768 limited the proliferation of several leukaemia cell lines, triggered significant changes in protein and mRNA levels related to CDK7 inhibition and induced apoptosis in dose- and time-dependent experiments. Our work supports previous findings and provides further information for the development of selective CDK7 inhibitors.
... Recently, other CDK7 inhibitors have been introduced, some of which have already entered clinical trials, namely, LY3405105, Q901 and XL102. Nevertheless, limited information about their mode of action, kinase selectivity or structure has been disclosed [19][20][21][22][23] We have previously reported several series of potent 3,5,7-trisubstitued pyrazolo [4,3d]pyrimidine CDK inhibitors with strong anticancer activity in vitro and in vivo [24][25][26][27]. ...
Targeting cyclin-dependent kinase 7 (CDK7) provides an interesting therapeutic option in cancer therapy because this kinase participates in regulating the cell cycle and transcription. Here, we describe a new trisubstituted pyrazolo[4,3- d ]pyrimidine derivative, LGR6768, that inhibits CDK7 in the nanomolar range and displays favourable selectivity across the CDK family. We determined the structure of fully active CDK2/cyclin A2 in complex with LGR6768 at 2.6 Å resolution using X-ray crystallography, revealing conserved interactions within the active site. Structural analysis and comparison with LGR6768 docked to CDK7 provides an explanation of the observed biochemical selectivity, which is linked to a conformational difference in the biphenyl moiety. In cellular experiments, LGR6768 affected regulation of the cell cycle and transcription by inhibiting the phosphorylation of cell cycle CDKs and the carboxy-terminal domain of RNA polymerase II, respectively. LGR6768 limited the proliferation of several leukaemia cell lines, triggered significant changes in protein and mRNA levels related to CDK7 inhibition and induced apoptosis in dose- and time-dependent experiments. Our work supports previous findings and provides further information for the development of selective CDK7 inhibitors.
Graphical abstract
... The development of novel anti-MCL approaches needs better elucidation of molecular factors involved in this malignancy. [7][8][9][10][11] Recent studies have identified several factors, such as the NF-κB signal pathway and CDK7, play critical roles in MCL and might serve as potential therapeutic targets for the treatment of MCL. 9,11 Circular RNAs (circRNAs) are emerging novel players in human cancers that regulate cancer progression mainly by affecting gene expression. ...
... [7][8][9][10][11] Recent studies have identified several factors, such as the NF-κB signal pathway and CDK7, play critical roles in MCL and might serve as potential therapeutic targets for the treatment of MCL. 9,11 Circular RNAs (circRNAs) are emerging novel players in human cancers that regulate cancer progression mainly by affecting gene expression. 12,13 Therefore, circRNAs are promising targets to treat cancers including MCL. ...
Background:
It was reported that circular RNA (circRNA) circCTNNA1 plays an oncogenic role in colorectal cancer, while its role in mantle cell lymphoma (MCL) is unknown. This study aimed to explore the role of circCTNNA1 in MCL.
Methods:
Samples of B lymphocytes were collected from 56 MCL patients and 56 healthy controls. The expression of circCTNNA1 and miR-34a in these samples were determined by RT-qPCR. The direct interaction between circCTNNA1 and miR-34a in MCL cells was detected using RNA-RNA pulldown assay. Overexpression assays were performed to study the interactions between circCTNNA1 and miR-34a. Cell proliferation was assessed with BrdU assay.
Results:
The results showed that circCTNNA1 was upregulated in MCL and high expression levels of circCTNNA1 predicted the poor survival of MCL patients. MiR-34a was downregulated in MCL and inversely correlated with circCTNNA1. CircCTNNA1 was predicted to interact with miR-34a, and the interaction between them was confirmed by RNA pull-down assay. Interestingly, overexpression of circCTNNA1 and miR-34a did not affect the expression of each other. Cell proliferation analysis showed that overexpression of circCTNNA1 reversed the inhibitory effects of overexpression of miR-34a on cell proliferation.
Conclusion:
Upregulation of circCTNNA1 in MCL predicts poor survival of patients and it may sponge miR-34a to promote cancer cell proliferation.
... 14,15 Recently, CDK7 has been increasingly recognized for its roles in breast cancer, T-cell acute lymphoblastic leukemia, gastric cancer, small cell lung cancer, neuroblastoma, and ovarian cancer. [15][16][17][18][19][20][21] As an anticancer target, inhibition of CDK7 simultaneously blocks DNA transcription and cell cycle progression. 7,15,16 There are several ongoing preclinal studies and clinical trials testing CDK7 inhibitors in advanced solid malignancies. ...
Background
Overexpression of cyclin-dependent kinase 7 (CDK7) is a well-known pathogenic feature of various malignancies and a sign of a more dismal prognosis. As relatively little is known about CDK7 in osteosarcoma, we elected to evaluate its expression, prognostic value, and function.
Methods
We began by analyzing the publicly available data sets on CDK7 expression, including RNA sequencing data from the Therapeutically Applicable Research to Generate Effective Treatments on Osteosarcoma (TARGET-OS) and the Gene Expression database of Normal and Tumor tissues 2 (GENT2). The correlation between patient tissue CDK7 expression and their clinicopathological features and prognosis was assessed via immunohistochemical staining of a unique tissue microarray constructed from osteosarcoma specimens. Furthermore, we analyzed CDK7 expression in osteosarcoma cell lines and tissues by Western blot. CDK7-specific siRNA and a highly-selective CDK7 inhibitor, BS-181, were applied to determine the function of CDK7 on osteosarcoma cell growth and proliferation. In addition, the effect of CDK7 inhibition on clonogenicity was evaluated using a clonogenic assay, and a 3D cell culture model was used to mimic CDK7 effects in an in vivo environment.
Results
Our results demonstrate that higher CDK7 expression significantly correlates with recurrence, metastasis, and shorter overall survival in osteosarcoma patients. Therapeutically, we show that CDK7 knockdown with siRNA or selective inhibition with BS-181 decreases proliferation and induces apoptosis of osteosarcoma cells.
Conclusion
This study supports CDK7 overexpression as an independent predictor of poor prognosis and promising therapeutic target for osteosarcoma.
... Specific inhibition of CDK2, CDK5, and CDK7 was tested in B-cells lymphoma cell lines. CDK2 inhibition by CVT-313 treatment or CDK2 siRNA induced apoptosis [233], CDK5 inhibition by CDK5-specific shRNAs reduced proliferation and increased apoptosis [234], and CDK7 inhibitor QS1189 induced apoptosis and cell cycle arrest [235]. ...
Ischemic stroke is the second leading cause of death worldwide. Following ischemic stroke, Neurovascular Unit (NVU) inflammation and peripheral leucocytes infiltration are major contributors to the extension of brain lesions. For a long time restricted to neurons, the 10 past years have shown the emergence of an increasing number of studies focusing on the role of Cyclin-Dependent Kinases (CDKs) on the other cells of NVU, as well as on the leucocytes. The most widely used CDKs inhibitor, (R)-roscovitine, and its (S) isomer both decreased brain lesions in models of global and focal cerebral ischemia. We previously showed that (S)-roscovitine acted, at least, by modulating NVU response to ischemia. Interestingly, roscovitine was shown to decrease leucocytes-mediated inflammation in several inflammatory models. Specific inhibition of roscovitine majors target CDK 1, 2, 5, 7, and 9 showed that these CDKs played key roles in inflammatory processes of NVU cells and leucocytes after brain lesions, including ischemic stroke. The data summarized here support the investigation of roscovitine as a potential therapeutic agent for the treatment of ischemic stroke, and provide an overview of CDK 1, 2, 5, 7, and 9 functions in brain cells and leucocytes during cerebral ischemia.
