Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors

Abstract

Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC 50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC 50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.

Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as novel and potent TBK1 inhibitors: design, synthesis, biological evaluation, and molecular docking study

“…The key intermediate 9 was prepared by a previously reported synthetic route, which was optimised moderately. 28 , 29 Then, palladium-catalysed C-N coupling reaction was utilised to obtain corresponding intermediates 10a – 10i . Subsequently, a palladium-catalysed Suzuki reaction between 10a – 10i and 1-methyl-4-[4–(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine were conducted to get intermediates 11a – 11i , and then the SEM protecting group was removed to yield the desired products 12a – 12i ( Scheme 1 ).…”

Fused Pyridine Derivatives: Synthesis and Biological Activities

“…Apart from these, many kinase inhibitors, namely CDK1/CDK2, glycogen synthase kinase-3, protein kinase Cθ (PKCθ), phosphatidylinositol-3-kinases (PI3K), aurora-A kinase, pim-kinase, TYK2, ALK5 (activin receptor-like kinase 5), anaplastic lymphoma kinase (ALK), and mitogen-activated protein kinase kinase 4 (MKK4) inhibitors, have pyrazolopyridine ring in their scaffold [223][224][225][226][227][228][229][230][231][232].…”

1H-Pyrazolo[3,4-b]pyridines: Synthesis and Biomedical Applications

“…Moreover, 51 shows a remarkable inhibition of ROS1 (IC 50 < 0.5 nM) and displays excellent selectivity over c-Met. 51 resolutely suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells boarding EML4-ALK via apoptosis and the ALK signaling blockade [ 128 ].…”