Structure-based drug design of a highly potent CDK1,2,4,6 inhibitor with novel macrocyclic quinoxalin-2-one structure

Kawanishi, Nobuhiko; Sugimoto, Tatsuho; Shibata, Jun; Nakamura, Kaori; Masutani, Kouta; Ikuta, Mari; Hirai, Hiroshi

doi:10.1016/j.bmcl.2006.07.026

Cited by 81 publications

(47 citation statements)

References 10 publications

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“…Macrocyclic quinoxalin-2-one compounds were found to show potent CDK inhibitory effects and were suitable for i.v. administration in vivo, as reported recently (23). In the present study, we characterized one macrocyclic quinoxalin-2-one compound (compound A) for anticancer efficacy.…”

Section: Resultsmentioning

confidence: 93%

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Expression levels of p18INK4C modify the cellular efficacy of cyclin-dependent kinase inhibitors via regulation of Mcl-1 expression in tumor cell lines

Eguchi

Itadani

Shimomura

et al. 2009

Molecular Cancer Therapeutics

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Because cyclin-dependent kinases (CDK) play a pivotal role in cancer progression, the development of CDK inhibitors has attracted attention in antitumor therapy. However, despite significant preclinical and clinical developments, CDK inhibition biomarkers for predicting efficacy against certain cancers in individual patients have not been identified. Here, we characterized a macrocyclic quinoxalin-2-one CDK inhibitor, compound A, and identified a gene biomarker for predicting its efficacy. Compound A showed 100-fold selectivity for CDK family proteins over other kinases and inhibited both E2F transcriptional activity and RNA polymerase II phosphorylation. Compound A treatment resulted in decreased proliferation in various tumor cell lines; however, the apoptosis induction rate differed significantly among the cell lines examined, which was consistent with roscovitine. By comparing the mRNA expression profiles of sensitive and resistant cell lines, we found that expression levels of an endogenous CDK inhibitor, p18 INK4C , showed a strong negative correlation to the sensitivity. In fact, p18 status was correlated with the response to CDK inhibitor in an independent data set of multiple myeloma cell lines and silencing p18 expression increased the susceptibility of resistant cells to CDK inhibitors. The analysis of molecular mechanisms revealed that cells with lowered p18 had aberrant CDK6 and E2F activities, which resulted in a transcriptional down-regulation of Mcl-1, a key molecule associated with flavopiridolinduced apoptosis, thereby leading to susceptibility to therapeutic intervention with CDK inhibitors. These results identified a molecular basis for CDK inhibitors to exert an antitumor effect in p18-deficient cancers and support the clinical use of CDK inhibitors.

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Section: Resultsmentioning

confidence: 93%

“…Chemistry Compound A is an analogue of macrocyclic quinoxalin-2-one CDK inhibitor (designated compound 13 in the previous report), which is substituted at the 7 position of quinoxalin-2-one by an aniline methyl group to increase cell potency (23).…”

Section: In Vitro Kinase Assaysmentioning

confidence: 99%

Expression levels of p18INK4C modify the cellular efficacy of cyclin-dependent kinase inhibitors via regulation of Mcl-1 expression in tumor cell lines

Eguchi

Itadani

Shimomura

et al. 2009

Molecular Cancer Therapeutics

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“…5 compares how a potent CDK4 inhibitor (PDB code: 1PU501) binds within the crystal structure of CDK4 that mimics CDK2 (PDB code: 1GIH, resolution 2.80 Å) with the way 5‘-Cl docks into the binding pocket of the same protein. Incidentally, inactive CDK2 monomer is closely homologous to CDK4 and therefore was used as a structural surrogate for CDK4 [39]. This approach is convenient since the crystal structure of CDK2 is known, and the crystals are particularly robust, often diffract to high resolution and can readily be soaked in inhibitor solutions enabling rapid experimental support for molecular design strategies.…”

Section: Resultsmentioning

confidence: 99%

The Anticancer Activity of the Substituted Pyridone-Annelated Isoindigo (5'-Cl) Involves G0/G1 Cell Cycle Arrest and Inactivation of CDKs in the Promyelocytic Leukemia Cell Line HL-60

Saleh

Aljada

El‐Abadelah

et al. 2015

Cell Physiol Biochem

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Background/Aims:The antileukemic potential of isoindigos make them desired candidates for understanding their mechanism of action. We have recently synthesized a novel group of pyridone-annelated isoindigos and identified the derivative 5'-Cl that is cytotoxic to various cancer cell lines. In the present study, we analyzed the effect of this compound on cell cycle of the promyelocytic leukemia cell line HL-60. Methods:HL-60 cells were treated with 5'-Cl and its effect on cell cycle stages were determined by flow cytometry. Expression of cyclins, cyclin dependent kinases (CDKs) and cyclin kinase inhibitors (CKIs) were determined by Western blotting, and activation of CDKs was studied using kinase assays. Results:5'-Cl remarkably arrested cell cycle in HL-60 cells at the G0/G1 phase in a dose and time-dependent manner. Furthermore, 5'-Cl treatment significantly inhibited expression of D-cyclins, CDK2 and CDK4 and suppressed phosphorylation of the retinoblastoma protein Rb, whereas it increased the level of CKI p21. Molecular modelling experiments show that 5'-Cl may compete with ATP for binding to the catalytic subunit of CDK2 and CDK4 that could lead to inhibition of these enzymes. Indeed, 5'-Cl inhibited the kinase activity of CDK2 and CDK4 both in cell free systems and in treated cells. 5'-Cl also inhibited cell cycle progression in several other tumor cell lines. Conclusion:We demonstrate the potent inhibitory effects of 5'-Cl on HL-60 cells could be mediated by arresting cells in the G0/G1 phase.

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“…1. Compound 1 is an analog of macrocyclic quinoxalin-2-one pan-Cdk inhibitor [18]. Compound 2 is a Cdk4/6 selective inhibitor reported previously [19,20].…”

Section: Compounds and Antibodiesmentioning

confidence: 99%

Cell death induction in resting lymphocytes by pan-Cdk inhibitor, but not by Cdk4/6 selective inhibitor

et al. 2010

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Immunosuppression is one of the common side effects of many anti-tumor agents targeting proliferating cells. We previously reported the development of a new class of pan-cyclin-dependent kinase (Cdk) inhibitor compounds that induce immunosuppression in rodents. Here, we demonstrated that a pan-Cdk inhibitor, Compound 1 very rapidly reduced white blood cells in mice, only 8 h after administration. Compound 1 induced death of peripheral blood cells or purified resting (non-stimulated) lymphocytes ex vivo. Cell death was induced very rapidly, after 4 h of incubation, suggesting that acute immunosuppression observed in rodents might be, at least in part, due to direct cytotoxic effects of Compound 1 on resting lymphocytes. While cell cycle-related Cdks were not activated, the carboxyl terminal domain (CTD) of the largest subunit of RNA polymerase II was phosphorylated, indicating activation of Cdk7 or Cdk9, which phosphorylates this domain, in resting lymphocytes. Indeed, the pan-Cdk inhibitor suppressed CTD phosphorylation in resting cells at the dose required for cell death induction. Inhibition of Cdk7 or Cdk9 by Compound 1 was also confirmed by suppression of nuclear factor-kappa B (NF-κB)-dependent transcription activity in the human cancer cell line U2OS. Interestingly, a Cdk4/6 inhibitor with selectivity against Cdk7 and Cdk9 did not induce cell death in resting lymphocytes. These results suggest that CTD phosphorylation possibly by Cdk7 or Cdk9 might be important for survival of resting lymphocytes and that Cdk inhibitors without inhibitory activity on these kinases might be an attractive agent for cancer chemotherapy.

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Structure-based drug design of a highly potent CDK1,2,4,6 inhibitor with novel macrocyclic quinoxalin-2-one structure

Cited by 81 publications

References 10 publications

Expression levels of p18INK4C modify the cellular efficacy of cyclin-dependent kinase inhibitors via regulation of Mcl-1 expression in tumor cell lines

Expression levels of p18INK4C modify the cellular efficacy of cyclin-dependent kinase inhibitors via regulation of Mcl-1 expression in tumor cell lines

The Anticancer Activity of the Substituted Pyridone-Annelated Isoindigo (5'-Cl) Involves G0/G1 Cell Cycle Arrest and Inactivation of CDKs in the Promyelocytic Leukemia Cell Line HL-60

Cell death induction in resting lymphocytes by pan-Cdk inhibitor, but not by Cdk4/6 selective inhibitor

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