De novo design, synthesis and pharmacological evaluation of new azaindole derivatives as dual inhibitors of Abl and Src kinases

Pharmacological and Molecular Effects of Platinum(II) Complexes Involving 7-Azaindole Derivatives

“…Moreover, the biological perspective of 7-azaindole moiety, as recently proved on various 7-azaindole derivatives reported as having notable biological properties, such as anticancer activity [18] , inhibition of kinases ( e.g . tropomyosin-related [19] or Abl and Src kinases [20] ) or antiviral effect [21] , has to be taken into account as well. Recently, we prepared and thoroughly characterized the platinum(II) dichlorido complexes involving 7-azaindole or its halogeno derivatives 3-chloro-7-azaindole (the complex 1 in this work), 3-iodo-7-azaindole ( 2 in this work) and 5-bromo-7-azaindole ( 3 in this work) (see Figure 1 ) and screened them for their in vitro antitumour activity against HOS osteosarcoma, MCF7 breast carcinoma and LNCaP prostate carcinoma human cancer cell lines with IC 50 equalled 1.5–8.0 µM [22] , [23] .…”

Rational Design, Synthesis, and Biological Evaluation of 7-Azaindole Derivatives as Potent Focused Multi-Targeted Kinase Inhibitors

“…Our series of compounds is composed of a 7-azaindole core that is considered an adenine mimetic heterocycle and is predicted to dock into the purine binding site by interacting with the hinge. As shown in a previous study, the addition of a first aromatic ring (best with methyl-substituted phenyl) to the 7-azaindole moiety with an aminomethyl linker allows interaction with the first hydrophobic pocket juxtaposed to the gatekeeper existing both in the active or inactive conformation. Accordingly, to design selective type-II inhibitors, a second aromatic moiety was added to the inhibitor structure to create new hydrophobic interactions with the second specificity pocket.…”

“…Medicinal Chemistry and Kinase Assays. Starting from the DFG-in series previously described, 8 the aim was to design compounds able to inhibit kinases belonging to the receptor tyrosine kinase family, the SRC family, and the MAPK pathway. We selected four representative kinases from the growth receptor tyrosine kinase family (EGFR, epidermal growth factor receptor; VEGFR2, vascular endothelial growth factor receptor 2; FGFR2, fibroblast growth factor receptor 2; PDGFRA, platelet-derived growth factor receptor alpha), SRC kinase as a representative member of the SRC family, and B-RAF kinase as one of the first kinases involved in the MAPK signaling pathway activation.…”

“…Using structure-based drug design combined with medicinal chemistry approaches, we have designed and synthesized a new and potent 7-azaindole-based chemical series showing a multitarget kinase inhibition profile. The compounds from the new series are all type-II inhibitors and are part of the follow-up series from the study of dual ABL and SRC kinase type-I inhibitors we published previously …”

“…The series was rationally designed according to a structure-based drug design and kinase-focused approach to identify single agents with an optimized multipharmacological inhibition profile. Recently, a series of DFG-in inhibitors was first designed and evaluated against kinases of the ABL and SRC families. , Using these DFG-in inhibitors composed of a 7-azaindole core as the initial fragment followed by iterative structural and kinase activity improvements, we have identified new type-II MTKIs that are highly potent against not only the ABL and SRC families but also other oncogenic kinase members of the receptor tyrosine kinase group and the MAPK pathway. Thus, the compounds target multiple kinase pathways involved in tumor progression, angiogenesis, immune system modulation, and metastasis.…”