Optimization of 3-Cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines Toward the Development of an In Vivo Chemical Probe for CSNK2A

Yang, Xuan; Ong, Han Wee; Dickmander, Rebekah J.; Smith, Jeffery L.; Brown, Jason W.; Tao, William C.; Chang, Edcon; Moorman, Nathaniel J.; Axtman, Alison D.; Willson, Timothy M.

doi:10.1101/2023.05.15.540828

Cited by 6 publications

(2 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…B1 proved to be very tolerant to microsomal exposure, demonstrated excellent stability (>85%) after 30 min, and was not prone to non-NADPH-dependent enzymatic degradation. This stability is not true for other kinase inhibitor scaffolds, which are significantly degraded after just 30 min ( Yang et al, 2023 ). Since compound B1 was found to have the required aqueous solubility and mouse liver microsomal stability, it was submitted for in vivo characterization.…”

Section: Resultsmentioning

confidence: 99%

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology

Castano,

Silvestre,

Wells

et al. 2023

eLife

Self Cite

View full text Add to dashboard Cite

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD have indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3b, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3b activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3b activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3b. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces post-synaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated, key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity and human neuropathology.

show abstract

Section: Resultsmentioning

confidence: 99%

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology

Castano,

Silvestre,

Wells

et al. 2023

eLife

Self Cite

View full text Add to dashboard Cite

show abstract

“…These efforts led to the identification of compound 6 (Figure 5), which exhibited potent antiviral activity with moderate rates of clearance in human primary hepatocytes. 55 The X-ray crystal structure compound 3 in the ATP binding site of CK2 [PDB ID 6Z83, Figure 6] indicated that the pyrazolopyrimidine core and 7-cyclopropylamine bind to Val116 in the hinge region. The propionamide group formed two H-bonds with the amino acid residues Lys68 and Asp175.…”

Section: ■ Ck2 Inhibitorsmentioning

confidence: 99%

Recent Advances in the Discovery of CK2 Inhibitors

Al-Qadhi,

Yahya,

El-Nassan

2024

ACS Omega

View full text Add to dashboard Cite

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.

show abstract

Identification of 4-(6-((2-methoxyphenyl)amino)pyrazin-2-yl)benzoic acids as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3

Galal,

Krämer,

Strickland

et al. 2024

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

Optimization of 3-Cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines Toward the Development of an In Vivo Chemical Probe for CSNK2A

Cited by 6 publications

References 33 publications

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology

Recent Advances in the Discovery of CK2 Inhibitors

Identification of 4-(6-((2-methoxyphenyl)amino)pyrazin-2-yl)benzoic acids as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3

Contact Info

Product

Resources

About