Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth

Oshima, Tsuyoshi; Niwa, Yoshimi; Kuwata, Keiko; Srivastava, Ashutosh; Hyoda, Tomoko; Tsuchiya, Yoshiki; Kumagai, Megumi; Tsuyuguchi, M.; Tamaru, Teruya; Sugiyama, Akiko; Ono, Nobuyuki; Zolboot, Norjin; Aikawa, Yuri; Oishi, Shunsuke; Nonami, Atsushi; Arai, Fumio; Hagihara, Shinya; Yamaguchi, Junichiro; Tama, Florence; Kunisaki, Yuya; Yagita, Kazuhiro; Ikeda, Masaaki; Kinoshita, Takayoshi; Kay, Steve A.; Itami, Kenichiro; Hirota, Tsuyoshi

doi:10.1126/sciadv.aau9060

Cited by 108 publications

(92 citation statements)

References 62 publications

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“…This likely provides a mechanism for the enhanced selectivity of most CLK1/2/4 inhibitors over closely-related CLK3. It is interesting to note that the most selective inhibitors including the casein kinase 2 alpha 1 (CK2α1) inhibitor GO289 47 , the dual PIM/DAPK3 inhibitor HS56 48 , the selective DAPK3 inhibitor HS94 and HS184 48 and the CLK inhibitor MU1210 27 do not significantly interact with the hinge back bone, but rather engage contacts at the back pocket particularly with the DFG-1 residue. Such binding modes have also been noted by the KLIFS database 49 .…”

Section: Resultsmentioning

confidence: 99%

DFG-1 residue controls inhibitor binding mode and affinity providing a basis for rational design of kinase inhibitor selectivity

Schroeder

Bullock

Fedorov

et al. 2020

Preprint

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ABSTRACTSelectivity remains a challenge for ATP-mimetic kinase inhibitors, an issue that may be overcome by targeting unique residues or binding pockets. However, to date only few strategies have been developed. Here we identify that bulky residues located N-terminal to the DFG motif (DFG-1) represent an opportunity for designing highly selective inhibitors with unexpected binding modes. We demonstrate that several diverse inhibitors exerted selective, non-canonical binding modes that exclusively target large hydrophobic DFG-1 residues present in many kinases including PIM, CK1, DAPK and CLK. Using the CLK family as a model, structural and biochemical data revealed that the DFG-1 valine controlled a non-canonical binding mode in CLK1, providing a rational for selectivity over the closely-related CLK3 which harbors a smaller DFG-1 alanine. Our data suggests that targeting the restricted back pocket in the small fraction of kinases that harbor bulky DFG-1 residues offers a versatile selectivity filter for inhibitor design.

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Section: Resultsmentioning

confidence: 99%

DFG-1 residue controls inhibitor binding mode and affinity providing a basis for rational design of kinase inhibitor selectivity

Schroeder

Bullock

Fedorov

et al. 2020

Preprint

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“…REV-ERB and ROR proteins compete for response element (RORE)/ Clock/Bmal1 transcription to control a new transcriptional cycle for nearly 24 h 21 Furthermore, it has been reported that circadian oscillations can be post-transcriptionally modified by casein kinase 1/2 (CK1/2) via the phosphorylation of PER2. 22,23 For example, CK1δ/ε is a priming kinase for PER2 phosphorylation and a Discordant mouse model caused by CK1δ/ε disruption in GABAergic neurons shows a long (27.4 hour) behavioral period. 24 Hence, the current view is that circadian rhythms are governed by a very complex system that works in a well-organized way to coordinate endogenous circadian rhythms in gene expression and physiological metabolism.…”

Section: Circadian Clocksmentioning

confidence: 99%

Circadian rhythms and obesity: Timekeeping governs lipid metabolism

Yao

et al. 2020

Journal of Pineal Research

110

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Almost all living organisms have evolved autoregulatory transcriptional‐translational feedback loops that produce oscillations with a period of approximately 24‐h. These endogenous time keeping mechanisms are called circadian clocks. The main function of these circadian clocks is to drive overt circadian rhythms in the physiology of the organisms to ensure that main physiological functions are in synchrony with the external environment. Disruption of circadian rhythms caused by genetic or environmental factors has long‐term consequences for metabolic health. Of relevance, host circadian rhythmicity and lipid metabolism are increasingly recognized to cross‐regulate and the circadian clock‐lipid metabolism interplay may involve in the development of obesity. Multiple systemic and molecular mechanisms, such as hormones (ie, melatonin, leptin, and glucocorticoid), the gut microbiome, and energy metabolism, link the circadian clock and lipid metabolism, and predictably, the deregulation of circadian clock‐lipid metabolism interplay can increase the risk of obesity, which in turn may exacerbate circadian disorganization. Feeding time and dietary nutrients are two of key environmental Zeitgebers affecting the circadian rhythm‐lipid metabolism interplay, and the influencing mechanisms in obesity development are highlighted in this review. Together, the characterization of the clock machinery in lipid metabolism aimed at producing a healthy circadian lifestyle may improve obesity care.

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“…Main off-targets of silmitasertib (1) reported to have antiproliferative effects are for example the cyclin-dependent kinase (CDK1) [43,44], PIM-1 protooncogene, serine/threonine kinase (PIM1) [45], Homeodomain-interacting protein kinase 3 (HIPK3) [46,47], TANK-binding kinase 1 (TBK1) [48] or FMS-like tyrosine kinase 3 (FLT3) [49,50]. More recently some more selective CK2 inhibitors have been reported, including GO289 by Oshima et al [51] or an allosteric inhibitor CAM4066 by Brear et al [18]. However, the allosteric inhibitors are still weak and would require optimization and the selectivity of GO289 has not been comprehensively assessed.…”

Section: Conclusion/discussionmentioning

confidence: 99%

Optimization of pyrazolo[1,5-a]pyrimidines lead to the identification of a highly selective casein kinase 2 inhibitor

Kraemer

Kurz

Berger

et al. 2020

Preprint

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Casein kinase 2 (CK2) is a constitutively expressed serine/threonine kinase that has a large diversity of cellular substrates. Thus, CK2 has been associated with a plethora of regulatory functions and dysregulation of CK2 has been linked to disease development in particular to cancer. The broad implications in disease pathology makes CK2 an attractive target. To date, the most advanced CK2 inhibitor is silmitasertib, which has been investigated in clinical trials for treatment of various cancers, albeit several off-targets for silmitasertib have been described. To ascertain the role of CK2 inhibition in cancer, other disease and normal physiology the development of a selective CK2 inhibitor would be highly desirable. In this study we explored the pyrazolo[1,5-a]pyrimidine hinge-binding moiety for the development of selective CK2 inhibitors. Optimization of this scaffold, which included macrocyclization, led to IC20 (31) a compound that displayed high in vitro potency for CK2 (KD = 12 nM) and exclusive selectivity for CK2. X-ray analysis revealed a canonical type-I binding mode for IC20. However, the polar carboxylic acid moiety that is shared by many CK2 inhibitors including silmitasertib was required for potency and reduced somewhat cellular activity. In summary, IC20 represents a highly selective and potent inhibitor of CK2, which can be used as a tool compound to study CK2 biology and potential new applications for the treatment of diseases.

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Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth

Abstract: We discovered a new CK2 inhibitor and revealed its mechanism of action, connecting the circadian clock and cancer regulation.

Cited by 108 publications

References 62 publications

DFG-1 residue controls inhibitor binding mode and affinity providing a basis for rational design of kinase inhibitor selectivity

DFG-1 residue controls inhibitor binding mode and affinity providing a basis for rational design of kinase inhibitor selectivity

Circadian rhythms and obesity: Timekeeping governs lipid metabolism

Optimization of pyrazolo[1,5-a]pyrimidines lead to the identification of a highly selective casein kinase 2 inhibitor

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