Potency assay (off target):
Selectivity within target family: Radiometric enzyme assays were run for CDKL1–4. When comparing the binding and enzymatic assay results, nearly 100-fold selectivity was observed for CDKL5 versus the most potently inhibited kinase, CDKL2. Inhibition of CDKL3 and CDKL4 by SGC-CAF382-1 was modest (IC50 = 2.1–2.7 µM), and this compound did not inhibit CDKL1.
Outside Target family: SGC-CAF382-1 was screened in DiscoverX scanMAX panel and all kinases with PoC ≤ 20 plus GSK3β were profiled using orthogonal binding or enzymatic assays. While SGC-CAF382-1 has a good selectivity score (S10 [1 µM] = 0.017; 7 kinases with PoC < 10 at 1 µM), several CDKs (CDK9, PCTK1/CDK16, PCTK2/CDK17, PCTK3/CDK18) are potently inhibited (IC50 ≤ 100 nM). Weaker inhibition of CDK7 as well as both GSK3α and GSK3β was noted. Analysis of biochemical data reveals potent binding/inhibition of CDKL5, CDK9, CDK16, CDK17, and CDK18, and a 44-fold selectivity window between CDKL5 and the next most potently inhibited kinase (CDK7).
