Flavones and flavonols may have clinical potential as CK2 inhibitors in cancer therapy

McCarty, Mark F.; Assanga, Simon Bernard Iloki; Luján, Lidianys Lewis

doi:10.1016/j.mehy.2020.109723

Cited by 26 publications

(15 citation statements)

References 170 publications

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“…Caused cell cycle arrest [362,[374][375][376][377]. Decreased cell viability and proliferation [378][379][380][381][382][383].…”

Section: Luteolinmentioning

confidence: 99%

“…The serine-threonine kinase CK2-overexpressed in all cancers where it promotes proliferation, spread, and survival-is inhibited by luteolin [383]. Luteolin induced apoptosis and inhibited the progression of rat prostate carcinogenesis in a transgenic rat for adenocarcinoma of prostate (TRAP) model in addition to a xenograft prostate cancer model where angiogenesis was also inhibited.…”

Section: Luteolinmentioning

confidence: 99%

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Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

Tomko

Whynot

Ellis

et al. 2020

Cancers

160

139

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In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings. Cannabinoids have been suggested and shown to be effective in the treatment of various conditions. In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis. However, the therapeutic use of cannabinoids is currently limited to the treatment of symptoms and pain associated with chemotherapy, while their potential use as cytotoxic drugs in chemotherapy still requires validation in patients. Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions. The potential anti-cancer effects of cannabinoids, terpenes and flavonoids, present in cannabis, are explored in this literature review.

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“…Caused cell cycle arrest [362,[374][375][376][377]. Decreased cell viability and proliferation [378][379][380][381][382][383].…”

Section: Luteolinmentioning

confidence: 99%

Section: Luteolinmentioning

confidence: 99%

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

Tomko

Whynot

Ellis

et al. 2020

Cancers

160

139

View full text Add to dashboard Cite

show abstract

“…Modifications of the macrocyclic and open scaffold led to improved selectivity within the Tm-Panel. Highest Tm-shifts for CK2α and CK2α' were observed for IC20 (31) and its macrocyclic derivative IC19 (32). Both compounds shared a carboxylic acid group at the pendant aromatic ring as well as a BOC-group located at the amine attached to the 5-position of the pyrazolo [1,5-a]pyrimidine.…”

Section: Pyrazolo[15-a]pyrimidines Proved To Be Potent Ck2 Inhibitors In Vitromentioning

confidence: 99%

“…A pyrazolo [1,5-a]pyrimidine lead compound has been developed by AstraZeneca, which has also been associated with significant off-target activity including low nanomolar activity on DYRK kinases, DAPKs, and HIPKs [30]. In addition, 4,5,6,7-tetrabromo-1H-benzimidazole [31] has been an important early tool compound stabilized by halogen bonds to the hinge back bone which, however, also showed considerable off-target activity similar to several natural products such as flavones and flavonols with weak CK2 activity and poor pharmacological properties [32]. Thus, despite intensive research on CK2 and their prominent role in the development of cancer and other diseases no selective chemical probes for these closely related kinases have been reported so far.…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we optimized pyrazolo [1,5-a]pyrimidines to yield highly selective inhibitors of CK2. The expansion of this scaffold yielded the macrocyclic compound IC19 (32) and its ring opened analogue IC20 (31) that showed excellent potency and selectivity on kinome wide selectivity screens (DiscoverX/Eurofins). NanoBRET TM target engagement assays demonstrated a robust cellular activity for both IC19 (32) and IC20 (31) in the single digit micromolar range.…”

Section: Introductionmentioning

confidence: 99%

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

Krämer

Kurz

Berger

et al. 2020

European Journal of Medicinal Chemistry

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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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Identification of potential natural product derivatives as CK2 inhibitors based on GA-MLR QSAR modeling, synthesis and biological evaluation

Xuan,

Zhou,

Yue

et al. 2024

Med Chem Res

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Flavones and flavonols may have clinical potential as CK2 inhibitors in cancer therapy

Cited by 26 publications

References 170 publications

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

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

Identification of potential natural product derivatives as CK2 inhibitors based on GA-MLR QSAR modeling, synthesis and biological evaluation

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