Development of Selective Clk1 and -4 Inhibitors for Cellular Depletion of Cancer-Relevant Proteins

In cancer cells, kinases of the Clk
family control the supply of full-length, functional mRNAs coding
for a variety of proteins essential to cell growth and survival. Thus,
inhibition of Clks might become a novel anticancer strategy, leading
to a selective depletion of cancer-relevant proteins after turnover.
On the basis of a Weinreb amide hit compound, we designed and synthesized
a diverse set of methoxybenzo­thiophene-2-carboxamides, of which
the N-benzylated derivative showed enhanced Clk1 inhibitory activity.
Introduction of a m-fluorine in the benzyl moiety
eventually led to the discovery of compound 21b, a potent
inhibitor of Clk1 and -4 (IC50 = 7 and 2.3 nM, respectively),
exhibiting an unprecedented selectivity over Dyrk1A. 21b triggered the depletion of EGFR, HDAC1, and p70S6 kinase from the
cancer cells, with potencies in line with the measured GI50 values. In contrast, the cellular effects of congener 21a, which inhibited Clk1 only weakly, were substantially lower.