Flavones and Flavonols may have Clinical Potential as CK2 Inhibitors in Cancer Therapy

McCarty, Mark F.

doi:10.17140/csmmoj-2-105

Cited by 4 publications

(8 citation statements)

References 37 publications

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“…In order to investigate the selectivity of the acyclic and macrocyclic pyrazolo[1,5-a]pyrimidines, we screened compounds (23-37) against a panel of 56 kinases using differential scanning fluorimetry (DSF, see Figure 2 and Table S1 (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 Inhibitormentioning

confidence: 99%

“…However, we typically observed a false positive rate of approximately 1% in kinome wide screens using KINOMEscan® technology, which makes follow-up verification necessary. Some targets were already verified in the DSF panel, which led us to believe that PAK1, PIM3, DAPK2 and GAK represented false positive hits for IC19 (32) and DYRK1A most likely being a false positive hit for IC20 (31). False positives are usually easily identified when highly related kinases isoforms are not inhibited by the investigated compound.…”

Section: = Number Of Hits Number Of Assaysmentioning

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%

“…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. However, while IC20 (31) represents a good cellular tool compound, the comparison with a NanoBRET TM lysed-cells assay revealed a significant drop in cellular activity that would need to be addressed in further optimization of this inhibitor class for in vivo use.…”

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

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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Section: Pyrazolo[15-a]pyrimidines Proved To Be Potent Ck2 Inhibitormentioning

confidence: 99%

Section: = Number Of Hits Number Of Assaysmentioning

confidence: 99%