Development of novel conformationally restricted selective Clk1/4 inhibitors through creating an intramolecular hydrogen bond involving an imide linker

An overview of cdc2‐like kinase 1 (Clk1) inhibitors and their therapeutic indications

“…However, the clinical application of many of the reported inhibitors—especially in the noncancer indications—is usually hampered by either their insufficient selectivity profiling or reported compromised selectivity against several off‐target kinases with highly similar ATP‐binding pockets; their inhibition may lead to numerous side effects due to the impairment of crucial physiological functions they are regulating. Only recently, a few Clk1 inhibitors have succeeded in achieving selectivity over those closely related kinases, particularly Dyrk1A, a key kinase in counteracting cardiac hypertrophy, namely compounds 25 , 44 , 59 , 61 , 62 , and 66 , eliciting selectivity indices of 34, 388, 48.5, 143, 60, and 69, respectively 18,66,131,158,159 . The use of such selective inhibitors may aid further studies to accurately determine the horizons of Clk biology and the therapeutic potential of their specific inhibition.…”

“…Furthermore, the separation of Clk1 activity from Clk2 was found to be another hard mission, as many of the most potent reported Clk1 inhibitors demonstrate significant coinhibition of Clk2. Only two very recently reported Clk1/4 inhibitors ( 61 ) and ( 62 ) exhibited unprecedented selectivity over Clk2 with 62‐ and 50‐times higher affinities towards Clk1 158 (Table 17).…”

“…The SAR of the presented series proved the importance of an intramolecular hydrogen bond between an ortho ‐methoxy group and the imide linker NH that is likely to stabilize a coplanar bioactive conformation. Such rigidization was explained by authors to minimize the entropic penalty of binding to the ATP pocket of Clk1 158 …”

“…Biological evaluation of compounds ( 61 ) and ( 62 ) for their ability to inhibit the growth of T24 cancer cells in vitro at a treatment dose of 15 μM revealed that ( 61 ) couldn't inhibit cell growth while ( 62 ) exhibited a GI 50 of 1.1 μM. The lack of cellular activity of ( 61 ) was attributed in part to its decreased cell permeability owing to its lower cLogP compared to compound ( 62 ) 158 …”

“…Such rigidization was explained by authors to minimize the entropic penalty of binding to the ATP pocket of Clk1. 158 Extended selectivity screening of compounds ( 61) and (62) showed that they exhibited minimal or no inhibition towards the most frequently reported off-target kinases including CK1, CK2, Dyrk2, Haspin, HIPK1, MLCK2, and STK17A. ( 61) and ( 62) also demonstrated more than 143-and 60-fold lower inhibition of Dyrk1A than of Clk1 respectively, surpassing the selectivity of the previously reported carboxamides ( 59) and ( 60), and that of most highly potent and selective Clk1 inhibitors described to date.…”