Probing 2H‐Indazoles as Templates for SGK1, Tie2, and SRC Kinase Inhibitors

Abstract

The broader and systematic application of a novel scaffold is often hampered by the unavailability of a short and reliable synthetic access. We investigated a new strategy for the design and synthesis of an array of N2‐substituted aza‐2H‐indazole derivatives as potential kinase inhibitors. Guided by a rational ligand alignment approach to qualify the so‐far underrepresented aza‐2H‐indazole scaffold, indazoles were connected at the N2 position with a phenyl spacer and an arylsulfonamide or amide linkage. Initial profiling against a panel of 30 kinases confirmed the in silico predicted selectivity bias. A synthesized focused library of 52 different aza‐2H‐indazole derivatives showed good initial selective inhibition against SGK1, Tie2, and SRC kinases, with the best representatives having IC50 values in the range of 500 nm. In a comparative computational study, these data were analyzed and rationalized in light of docking studies.

Current progress, challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer

“…48 ) as potential inhibitors of SGK1, Tie2 and SRC. 176 All the synthesized compounds showed at least 70% inhibition against at least one of the three kinases with almost equivalent activity against SGK1 and Tie2 (98a–d, 98f and 99a and b). 2-Fluoro-3-chloro-substitution and 2,3-dichloro derivatives were found to be superior to the unsubstituted phenyl derivatives.…”

Medicinal Chemistry Perspectives on Recent Advances in Src Kinase Inhibitors as a Potential Target for the Development of Anticancer Agents: Biological Profile, Selectivity, Structure‐Activity Relationship

“…33 indicated the higher inhibition activity against SGK1 (IC 50 : 0.795 μM) and Tie2 (IC 50 : 1.12 μM) kinases but 0 % inhibition of Src kinase enzyme. [39] Rezaei et al 5.25 μM) and Lck (IC 50 : > 125 μM) kinases. The oxygen atoms of derivative 35 formed two hydrogen bonds with Lys298 and Asp351 amino acid residues of Src kinase.…”

Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis

“…Moreover, further evidence of the causal implication of SGK in the pathogenesis of degenerative cartilage changes exists . Despite the highly relevant biological function of SGK1, very few potent and selective inhibitors have been reported, and therefore, chemical tools for the further elucidation and validation of the biological role of SGK1 are needed. − We have previously described a series of highly potent N -[4-(1 H -pyrazolo­[3,4- b ]­pyrazin-6-yl)­phenyl]-sulfonamides that were discovered by a focused DFG-out screening assisted by ligand-based virtual screening approaches using ligand interaction models from known SGK1 inhibitors and library chemistry . Examples such as 1 and 2 (Figure ) exhibited very attractive selectivity and in vitro and pharmacokinetic profiles.…”