Cyclin G-associated kinase (GAK) affinity and antiviral activity studies of a series of 3-C-substituted isothiazolo[4,3-b]pyridines

A Scaffold‐Hopping Strategy toward the Identification of Inhibitors of Cyclin G Associated Kinase

“…In contrast, the introduction of an aryl group via palladium‐catalyzed Suzuki cross‐coupling reaction proceeded smoothly. Therefore, compound 5 , characterized by the presence of a phenyl moiety at position 3 (instead of the morpholine residue of compound 4 ) was used for comparison purposes . Although, GAK affinity of compound 5 ( K d : 0.77 μ m ) is 15‐fold lower than the corresponding 3‐morpholino analogue 4 , the straightforward synthesis of various phenyl‐substituted scaffold analogues justifies its use as a reference compound.…”

“…For some of the scaffolds (such as the pyrazolo [1,5-a]pyrimidine, pyrrolo [3,2-b]pyridine, pyrazolo [4,3-b]pyri-dine, and thieno [3,2-b]pyridine), the insertion of am orpholine residue via either an ucleophilic aromatic substitution, ap alladium-catalyzed Buchwald reaction or aC uI/l-proline mediated amination was cumbersome.I nc ontrast, the introduction of an aryl group via palladium-catalyzed Suzuki cross-coupling reaction proceeded smoothly.T herefore, compound 5,c haracterized by the presence of ap henyl moiety at position 3( instead of the morpholine residue of compound 4)w as used for comparisonp urposes. [19] Although, GAK affinity of compound 5 (K d : 0.77 mm)i s1 5-fold lower than the corresponding 3-morpholino analogue 4,t he straightforward synthesis of various phenylsubstituted scaffold analogues justifiesi ts use as ar eference compound. As the substitution pattern is kept intact, the influence of scaffold modification on GAK affinity can be easily studied.…”

Quantitative Proteomics Analysis of FFPE Tumor Samples Reveals the Influences of NET-1 siRNA Nanoparticles and Sonodynamic Therapy on Tetraspanin Protein Involved in HCC

“…The Q00534 (cyclin-dependent kinase 6) protein (red arrow in Figure 8 ) could regulate the other 11 proteins, such as O60884 (DNAJA2), O14976 (GAK) and so on. GAK is a cellular serine/threonine kinase that plays a major role in clathrin-mediated membrane trafficking ( Wouters et al, 2019 ). It has been proved that osteosarcoma cell proliferation and survival are dependent on GAK ( Susa et al, 2010 ).…”

Discovery of 3-phenyl- and 3-N-piperidinyl-isothiazolo[4,3-b]pyridines as highly potent inhibitors of cyclin G-associated kinase

“…In the present study, the 4-amino-3-methoxyphenyl moiety at position 6 of the isothiazolo [4,3-b]pyridine scaffold was fixed, as it was previously shown that electron-donating substituents (such as methoxy or amino groups) on the phenyl ring were optimal for GAK affinity and antiviral activity [29]. Previous molecular modelling demonstrated that an appropriate substitution pattern at position 3 of the scaffold can engage in additional interactions with Lys69 of GAK [31]. Given the synthetic feasibility, we opted for the insertion of phenyl and piperidine residues at position 3 of the isothiazolo [4,3-b]pyridine scaffold, and inserted carboxamide groups at different positions in order to exploit hydrogen bond interactions.…”

“…In order to expand the structural variety at position 3 of the isothiazolo [4,3-b]pyridine skeleton, we previously applied various palladium-catalyzed cross-couplings such as Suzuki and Sonogashira reactions. This effort led to the discovery of 3,6-bis (3,4dimethoxyphenyl)isothiazolo [4,3-b]pyridine 3, that was endowed with strong affinity for GAK (K D ¼ 41 nM) [31]. Molecular docking showed that the 3,4-dimethoxyphenyl residue at position 3 forms an additional hydrogen bond with Lys69 of the GAK enzyme.…”