Project Overview: Work towards a CLK probe

Hello everyone! This is my first post on the blog and I am going to give a brief summary of my main project as a Postdoctoral Research Associate at SGC-UNC. Protein phosphorylation is a quick and reversible mechanism with the aim to control biological functions. This mechanism involves structural conformational changes by adding a phosphate group (often taken from ATP) at certain sites of protein by protein kinase catalysis (Figure 1). While, phosphorylation usually occurs on serine and threonine residues; tyrosine residues are also phosphorylated in a small proportion. Chemical probes are essential because they can inhibit kinase functions and therefore, biological activities can be suppressed. So my primary goal is to develop kinase chemical probes in conjunction with my supervisor at SGC-UNC, David H. Drewry, and Luceome Biotechnologies in Tucson, AZ.

Figure 1. Protein Phosphorylation/Dephosphorylation.

Previously, GW807982X was identified to be a potent CLK2 inhibitor, giving a narrow inhibition profile. At a screening concentration of 1 μM, it was found that GW807982X only inhibits 3 kinases with an inhibition greater than 50%. With these previous studies, we synthesized a series of analogues with the purpose to explore the SAR and potentially identify a CLK1/CLK2 probe. The synthesis of the analogues is exemplified in Figure 2, and they are going to be screened at Luceome Biotechnologies. For compounds that show an inhibition >75% they are going to be further analyzed and dose responses curves are going to be generated to get IC50 values. To date, 32 analogues have been successfully synthesized, and hopefully, on my next post, once the results are back, we will be able to see if there is any activity on the analogues we prepared and the Structure-Activity Relationship with CLK kinases will be examined.

Figure 2. General scheme for the synthesis of GW807982X analogues.

To conclude this post, I want to thank David H. Drewry for his support and advice during my firsts months in the US. Today, December the 23rd, is time for a break. I am going back to Spain to spend the Christmas holidays with my family. Happy holidays everyone!!

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