Discovery of a Potent and Selective Naphthyridine-Based Chemical Probe for Casein Kinase 2

Davis-Gilbert, Zachary W.; Krämer, Andreas; Dunford, J E; Howell, Stefanie; Senbabaoglu, Filiz; Wells, Carrow; Potjewyd, Frances; Havener, Tammy M.; Smith, Jeffery L.; Hossain, Mohammad Anwar; Oppermann, Udo; Drewry, David H.; Axtman, Alison D.

doi:10.1021/acsmedchemlett.2c00530

Cited by 13 publications

(30 citation statements)

References 36 publications

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“…The π-stacking interaction between the phenyl ring and His160 was observed (Figure 4). 52 The pyrazolopyrimidine inhibitor 3 (SGC-CK2-1, Figure 5) was identified by Wells et al in 2020 as a highly potent CK2 inhibitor. 53,54 The amide group was responsible for the effective binding to the enzyme.…”

Section: ■ Ck2 Inhibitorsmentioning

confidence: 99%

Recent Advances in the Discovery of CK2 Inhibitors

Al-Qadhi,

Yahya,

El-Nassan

2024

ACS Omega

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CK2 is a vital enzyme that phosphorylates a large number of substrates and thereby controls many processes in the body. Its upregulation was reported in many cancer types. Inhibitors of CK2 might have anticancer activity, and two compounds are currently under clinical trials. However, both compounds are ATP-competitive inhibitors that may have offtarget side effects. The development of allosteric and dual inhibitors can overcome this drawback. These inhibitors showed higher selectivity and specificity for the CK2 enzyme compared to the ATP-competitive inhibitors. The present review summarizes the efforts exerted in the last five years in the design of CK2 inhibitors.

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Section: ■ Ck2 Inhibitorsmentioning

confidence: 99%

Recent Advances in the Discovery of CK2 Inhibitors

Al-Qadhi,

Yahya,

El-Nassan

2024

ACS Omega

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“…Diffraction data were collected at beamline X06SA (SLS, Villigen, CH) at a wavelength of 1.0 Å at 100 K. Data were integrated using XDS and scaled with aimless . The PDB structures with the accession codes 8BGC (CSNK2A1) and 6ZLN (CLK1) were used as an initial search MR model using the program MOLREP . The final model was built manually using Coot with iterative refinement steps of phenix.refine or REFMAC5 Data collection and refinement statistics are summarized in SI Table S5.…”

Section: Experimental Proceduresmentioning

confidence: 99%

Leucettinibs, a Class of DYRK/CLK Kinase Inhibitors Inspired by the Marine Sponge Natural Product Leucettamine B

et al. 2023

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Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) recently attracted attention due to their central involvement in various pathologies. We here describe a family of DYRK/CLK inhibitors derived from Leucettines and the marine natural product Leucettamine B. Forty-five N2functionalized 2-aminoimidazolin-4-ones bearing a fused [6 + 5]-heteroarylmethylene were synthesized. Benzothiazol-6-ylmethylene was selected as the most potent residue among 15 different heteroarylmethylenes. 186 N2-substituted 2-aminoimidazolin-4-ones bearing a benzothiazol-6-ylmethylene, collectively named Leucettinibs, were synthesized and extensively characterized. Subnanomolar IC 50 (0.5−20 nM on DYRK1A) inhibitors were identified and one Leucettinib was modeled in DYRK1A and cocrystallized with CLK1 and the weaker inhibited off-target CSNK2A1. Kinase-inactive isomers of Leucettinibs (>3−10 μM on DYRK1A), named iso-Leucettinibs, were synthesized and characterized as suitable negative control compounds for functional experiments. Leucettinibs, but not iso-Leucettinibs, inhibit the phosphorylation of DYRK1A substrates in cells. Leucettinibs provide new research tools and potential leads for further optimization toward therapeutic drug candidates.

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“…The pyrazolo[1,5- a ]pyrimidine SGC-CK2-1 is a high-quality chemical probe for CSNK2A that demonstrated cellular target engagement at 20 nM and had remarkable selectivity across the DiscoverX KinomeSCAN assay panel of >400 human kinases, with 90% inhibition of only CSNK2A1, CSNK2A2, and STK17B at 1 µM [3]. Silmitasertib (CX-4945) is a widely studied CSNK2A inhibitor from the benzo[c][2,6]naphthyridine chemotype that is in Phase 2 clinical development for treatment of rare cancers [4,5]. Compared to SGC-CK2-1, silmitasertib was about 10-fold less potent as an inhibitor of CSNK2A in cells and much less selective across the kinome (Table 1).…”

Section: Introductionsmentioning

confidence: 99%

Synthesis of 5-Benzylamino and 5-Alkylamino-substituted Pyrimido[4,5-c]quinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity

Asressu,

Smith,

Dickmander

et al. 2024

Preprint

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A series of 5-benzylamine-substituted pyrimido[4,5-c]quinoline derivatives of the CSNK2A chemical probe SGC-CK2-2 were synthesized with the goal of improving kinase inhibitor cellular potency and antiviral phenotypic activity while maintaining aqueous solubility. Among the range of analogs, those bearing electron-withdrawing (4cand4g) or donating (4f) substituents on the benzyl ring as well as introduction of non-aromatic groups such as the cyclohexylmethyl (4t) were shown to maintain CSNK2A activity. The CSNK2A activity was also retained withN-methylation of SGC-CK2-2, but α-methyl substitution of the benzyl substituent led to a 10-fold reduction in potency. CSNK2A inhibition potency was restored with indene-based compound4af, with activity residing in the S-enantiomer (4ag). Analogs with the highest CSNK2A potency showed good activity for inhibition of Mouse Hepatitis Virus (MHV) replication. Conformational analysis indicated that analogs with the best CSNK2A inhibition (4t, 4ac, and4af) exhibited smaller differences between their ground state conformation and their predicted binding pose. Analogs with reduced activity (4ad, 4ae, and4ai) required more substantial conformational changes from their ground state within the CSNK2A protein pocket.

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Discovery of a Potent and Selective Naphthyridine-Based Chemical Probe for Casein Kinase 2

Cited by 13 publications

References 36 publications

Recent Advances in the Discovery of CK2 Inhibitors

Recent Advances in the Discovery of CK2 Inhibitors

Leucettinibs, a Class of DYRK/CLK Kinase Inhibitors Inspired by the Marine Sponge Natural Product Leucettamine B

Synthesis of 5-Benzylamino and 5-Alkylamino-substituted Pyrimido[4,5-c]quinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity

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