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Title: Design, synthesis and biological evaluation of inhibitors of FGFR, VEGFR-2 and Ras proteins
Author: Jayakanth, Kankanala
ISNI:       0000 0004 2714 6579
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2011
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Deregulation of kinase activity has emerged as a major mechanism by which cancer cells evade normal physiological functions such as growth and survival. The identification of mutations in FGFR-3 within non invasive tumours of bladder cancer and over expression of this receptor in invasive tumours and superficial tumours makes FGFR-3 a promising target in developing a therapy for the treatment of urothelial bladder cancer. It was found that inhibiting VEGFR-2 together with FGFR provides an attractive strategy for the development of new anti-angiogenic agents as a potential anti -cancer therapy. In this project, the three dimensional structure of both the FGFR and VEGFR-2 was used in conjunction with the de novo methods such as SPROUT to generate oxindole- based novel inhibitors of FGFR and VEGFR-2 with ICso values in the range of 1-10 flM (Compound 4.7 inhibits FGFR and VEGFR-2 with ICso values of 3.9 uM and 1.6 flM for respectively (Chapter 4). These compounds show encouraging anti-angiogenic activity in the lower u M concentrations. In Chapter 5, intramolecular H-bonding concept was used to design pyrazole-based inhibitors of FGFR and VEGFR-2 with 29% and 63% inhibition at 10 uM respectively. Benzo-fused designs based on pyrazole scaffolds yielded indazole based compounds with inhibitory effects of 45%, 41 % and 74% for FGFR-1, FGFR-3 and VEGFR-2 respectively. Shape similarity was used to find novel hinge binders replacing the indazole core with hydroxy-quinolinone moiety which showed an encouraging level of inhibition with 30% and 64% for FGFR and VEGFR-2 respectively. Purine based inhibitors were designed to exploit the smaller gatekeeper residue in both the FGFR and VEGFR-2, but all the compounds show weaker or no inhibition at 10 u M (Chapter 5). In Chapter 6, structure guided method were used to design oxadiazole-based novel VEGFR-2 inhibitor with an ICso value of 1.6 j.1M. All these approaches are novel used in complementary to HTS. In Chapter 3, SPROUT was used to design novel inhibitors of Ras protein and the preliminary analysis of these inhibitors show preferential binding of these inhibitors to the active form compared to the inactive form. These molecules were first amongst the de novo/designed inhibitors of Ras which could serve as a starting point f-or the future potential inhibitors of protein-protein interaction.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available