Biological characterization of 2-aminothiazole-derived Cdk4/6 selective inhibitor in vitro and in vivo

Hirai, Hiroshi; Shimomura, Toshiyasu; Kobayashi, Makiko; Eguchi, Tomohiro; Taniguchi, Eiichi; Fukasawa, Kazuhiro; Machida, Takumitsu; Oki, Hiroko; Arai, T.; Ichikawa, Kunihiko; Hasako, Shinichi; Haze, Kyosuke; Kodera, Tsutomu; Kawanishi, Nobuhiko; Takahashi-Suziki, Ikuko; Nakatsuru, Yoko; Kotani, Hidehito; Iwasawa, Yoshikazu

doi:10.4161/cc.9.8.11306

Cited by 12 publications

(7 citation statements)

References 29 publications

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“…1b). The in vitro and in vivo biological characteristics of this compound are quite different from those of the pan-Cdk inhibitors Compound 1 and M. When used at concentrations of 0.1-1 µM, it induced cell cycle arrest selectively at the G1 phase in human leukemia cell lines such as Eol-1 in vitro [20]. In rats, it did not cause immunosuppression even at a dose 10 times higher than that necessary to inhibit pRb phsophorylation in xenograft tumors [20].…”

Section: The Cdk4/6-selective Inhibitor Does Not Induce Cell Death Inmentioning

confidence: 95%

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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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Section: The Cdk4/6-selective Inhibitor Does Not Induce Cell Death Inmentioning

confidence: 95%

“…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]. 5, 6-Dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) was purchased from Calbiochem (Cat.…”

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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“…The cyclin-dependent kinases (CDKs) are members of serine-threonine kinases that regulate the cell cycle and affect cell proliferation and apoptosis ( Braun et al, 1998 ; Diani et al, 2009 ; Szwarcwort-Cohen et al, 2009 ; Chung and Bunz, 2010 ; Hirai et al, 2010 ; Li et al, 2010 ; Duan et al, 2015 ; Rainey et al, 2017 ; Czudor et al, 2018 ; Menzl et al, 2019 ; Liang et al, 2020 ; Loyer and Trembley, 2020 ; Robert et al, 2020 ). They bind to their corresponding cyclin, forming a cyclin-CDK complex, where CDKs catalyze the phosphorylation of certain serine and threonine residues in target proteins, leading to regulation of gene transcription and cell division ( Rank et al, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

Ribociclib Inhibits P-gp-Mediated Multidrug Resistance in Human Epidermoid Carcinoma Cells

Zhang

Lin

et al. 2022

Front. Pharmacol.

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The efficacy of cancer chemotherapy can be attenuated or abrogated by multidrug resistance (MDR) in cancer cells. In this study, we determined the effect of the CDK4/6 inhibitor, ribociclib (or LEE011), on P-glycoprotein (P-gp)-mediated MDR in the human epidermoid carcinoma MDR cell line, KB-C2, which is widely used for studying P-gp-mediated MDR in cancers. The incubation of KB-C2 cells with ribociclib (3–9 µM) increased the efficacy of colchicine, a substrate for P-gp. The cell expression of P-gp was down-regulated at both translation and transcription levels. Furthermore, ribociclib produced a 3.5-fold increase in the basal activity of P-gp ATPase, and the concentration required to increase basal activity by 50% (EC50) was 0.04 μM. Docking studies indicated that ribociclib interacted with the drug-substrate binding site of P-gp. The short-term and long-term intracellular accumulation of doxorubicin greatly increased in the KB-C2 cells co-cultured with ribociclib, indicating ribociclib inhibited the drug efflux activity of P-gp. The results of our study indicate that LEE011 may be a potential agent for combined therapy of the cancers with P-gp mediated MDR.

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“…Cdk4/6 is an attractive target for cancer therapy. Thus, a 2-aminothiazole-derived Cdk4/6 selective inhibitor, named Compound A potently inhibits Cdk4 and Cdk6 with high selectivity [99]. Among 82 human cell line examined, leukemia and lymphoma cell lines tended to be more sensitive to Compound A.…”

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confidence: 99%

“…In a nude rat xenograft model, Compound A inhibited cell proliferation in xenograft tumors at a plasma concentration of 510 nM. Compound A only moderately inhibited cell cycle progression of normal crypt cells in small intestine even at 5 times higher plasma concentration and did not cause immunosuppression even at 17 times higher concentration [99]. …”

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confidence: 99%

Recent progress in targeting cancer

Demidenko

McCubrey²

2011

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Biological characterization of 2-aminothiazole-derived Cdk4/6 selective inhibitor in vitro and in vivo

Cited by 12 publications

References 29 publications

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

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

Ribociclib Inhibits P-gp-Mediated Multidrug Resistance in Human Epidermoid Carcinoma Cells

Recent progress in targeting cancer

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