The importance of angiogenesis for solid tumor growth is well recognized and evident by the vast differential of research devoted to the subject for over thirty years. It is a complex process directed by growth factors, receptors, extracellular matrix (ECM)-to-cell and cellto- cell interactions. Tyrosine kinase (TKs) is the protein enzymes catalyze the transfer of a phosphate group from an ATP molecule to a tyrosine residue of the target protein, thus leading to signal transduction. Cytoplasmic TKs such as Src, Abl and Lck have been to date discovered and characterized and found that inhibition signalling pathway. A special Src protein like FAK is a non-receptor protein-tyrosine kinase which have vital role in various cellular function like cytoskeleton reorganization, migration, adhesion, spreading, configuration and destruction of FA, cell protrusions, progression, proliferation and apoptosis. The functional ateration of Src signal may be the reason for cancer and metastasis. So this can predict that Src and their signal inhibition can utilized in cancer therapy. Triazine containing hybrid analogues act as a prime skeleton to inhibit Src family TKs like FAK so in present project we constructed 1,3,5-triazine containing analogues (TCA) as an effective cancer induced angiogensis inhibitor.
TCA analogues constructed accordingly similarity field positioning and pattern through forge V10. Further more in-silico simulation was done using autodock for most prominent analogues. The analogues derived via multifactorial synthetic protocol. The activity evaluation proceeded via in-vitro assay against MCF-7 (Breast cancer) cell line and further in-ova antiangiogenic potency evaluated against cancer induced chick chorioallantoic membrane.
The newly designed and constructed TCA heterocycles expressed more than 56% of similar field point pattern and intra atomic alignments. The prominent pattern showed by the analogue 8d (chloro-anilino) and 8k (bromo-anilino). In-silico docking on hydrophobic site of Src family protein (PDB: 4BRX) revealed that analogue 8d have binding with CYS502, TR503, GLU506, ILE428, ASN551 while analogue 8k shoed interaction with THR503, GLU506, ILE428, LEU567, ASN551 amino acid residue which was similar like vendatinib. Biological evaluation showed that analogues 8d and 8k have great tendency to inhibit cancer induced angiogenesis with marginal toxicity profile.
We have developed a significant series of anticancer analogues and propound the site of binding on the surface of Src family TKs receptor FAK.
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All authors have declared no conflicts of interest.