Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance

Kaliszczak, Maciej; Patel, Hetal; Kroll, Sebastian H. B.; Carroll, Laurence; Smith, Graham; Delaney, Sean W.; Heathcote, Dean A.; Bondke, Alexander; Fuchter, Matthew J.; Coombes, R. Charles; Barrett, Anthony G. M.; Ali, Simak; Aboagye, Eric O.

doi:10.1038/bjc.2013.584

Cited by 21 publications

(22 citation statements)

References 49 publications

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“…[30,31,33,[37][38][39][40] We have previously reported the identification of severalCDK inhibitory compounds,includingamolecule selective for CDK7. [25,37,41] Here, we use acombination of structural, biophysical and modelling techniques to develop an understanding of the selectivity of representative inhibitors for CDK7 over CDK2. We have focused on three inhibitors from our compound library,t wo of which are CDK7 selective, and one which is CDK2 selective.…”

Section: Introductionmentioning

confidence: 99%

Inhibitor Selectivity for Cyclin‐Dependent Kinase 7: A Structural, Thermodynamic, and Modelling Study

et al. 2017

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Table of contents entryWe have solved crystal structures of CDK7--selective inhibitors bound to CDK2.We have used a combination of structural, biophysical and modelling approaches to model the binding of these inhibitors to CDK7, and have used this information to explain their selectivity. We identify specific CDK7 residues that contribute to these inhibitors' specificity. AbstractDeregulation of the cell cycle by mechanisms that lead to elevated activities of cyclin--dependent kinases (CDK) is a feature of many human diseases, in particular cancer. We have identified small molecule inhibitors that selectively inhibit CDK7, the kinase that phosphorylates cell cycle CDKs to promote their activities. To investigate the selectivity of these inhibitors we have used a combination of structural, biophysical and modelling approaches. We have determined crystal structures of the CDK7 selective compounds ICEC0942 and ICEC0943 bound to CDK2, and used these to build models of inhibitor binding to CDK7. Molecular dynamics simulations of inhibitors bound to CDK2 and CDK7 have generated possible models of inhibitor binding. In order to experimentally 3 validate these models, we measured isothermal titration calorimetry (ITC) binding data for recombinant wild type and binding site mutants of CDK7 and CDK2. We have identified specific residues of CDK7, notably Asp155, that are involved in determining inhibitor selectivity. Our molecular dynamics simulations also show that the flexibility of the G--rich and activation loops of CDK7 is likely an important determinant of inhibitor specificity similar to CDK2.4

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Section: Introductionmentioning

confidence: 99%

Inhibitor Selectivity for Cyclin‐Dependent Kinase 7: A Structural, Thermodynamic, and Modelling Study

et al. 2017

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“…The first generation of CDK inhibitors has entered late-stage clinical trials but so far has only shown modest activity because of unfavorable pharmacology. 6 Most of the CDK inhibitors target the highly conserved kinase domain and could inhibit multiple CDK family members, which in part explain the undesirability of those trials. Hence, the identification of more selective and potent CDK inhibitors is imperative.…”

Section: Introductionmentioning

confidence: 99%

Selective CDK7 inhibition with BS-181 suppresses cell proliferation and induces cell cycle arrest and apoptosis in gastric cancer

Wang

Liu

Cao

et al. 2016

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Cyclin-dependent kinase (CDK) family members have been considered as attractive therapeutic targets for cancer. In this study, we aim to investigate the anticancer effects of a selective CDK7 inhibitor, BS-181, in gastric cancer (GC) cell line. Human GC cells (BGC823) were cultured with or without BS-181 at different concentrations for 24–72 hours. BS-181 significantly reduced the activity of CDK7 with downregulation of cyclin D1 and XIAP in GC cells. Treatment with BS-181 induced cell cycle arrest and apoptosis. The expression of Bax and caspase-3 was significantly increased, while Bcl-2 expression was decreased in cells treated with BS-181. In addition, the inhibition of CDK7 with BS-181 resulted in reduced rates of proliferation, migration, and invasion of gastric cells. Those results demonstrated the anticancer activities of selective CDK7 inhibitor BS-181 in BGC823 cells, suggesting that CDK7 may serve as a novel therapeutic target or the treatment of GC.

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“…Our study confirms these mechanisms and extends these findings to breast cancer. This is the first study designed to investigate mechanisms of resistance to ICEC0942, although both ABCB1 and ABCG2 have been implicated in resistance to the pan-CDK inhibitor BS-194, a chemically-related precursor to ICEC0942 [40]. Our present study suggests that the structural differences between BS-194 and ICEC0942 have resulted in a reduced affinity of ABCG2 for ICEC0942 compared with BS-194.…”

Section: Discussionmentioning

confidence: 66%

ABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942

et al. 2019

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The CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was upregulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin-and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.

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Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance

Cited by 21 publications

References 49 publications

Inhibitor Selectivity for Cyclin‐Dependent Kinase 7: A Structural, Thermodynamic, and Modelling Study

Inhibitor Selectivity for Cyclin‐Dependent Kinase 7: A Structural, Thermodynamic, and Modelling Study

Selective CDK7 inhibition with BS-181 suppresses cell proliferation and induces cell cycle arrest and apoptosis in gastric cancer

ABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942

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