Fragment Based Approach in the Search for New Kinase Inhibitors

Abstract

This master's thesis have been performed in cooperation with a larger researchgroup, as part of an ongoing study. The group is engaged in developing biologicallyactive compounds with potency of inhibiting epidermal growth factorreceptor tyrosine kinase (EGFR TK), for potential use as anti-cancer agents.The primary goal of this master's thesis has been the identification of new activeEGFR tyrosine kinase inhibitors. This has been done by use of a fragment basedapproach. Selected aniline fragments present in commercially available EGFRinhibitors have been introduced to a thienopyrimidine scaffold, forming buildingblocks for further combination with potency inducing fragments identified by theresearch group. A total of nine target compounds and one building block havebeen synthesized in this work.The target compounds have been synthesized from 1 using a thermal aminationsucceeded by a Suzuki cross-coupling reaction. Compounds 8c, 14c and 15cwere obtained by reducing the formyl group in 8b, 14b and 15b, respectively.The building blocks 4 and 5 had been prepared earlier, but were used in furthersyntheses in this work. The aniline fragment found in 13 has also been made inthis thesis work. Owing to dimerization of the product, compound 15a had tobe synthesized using an alternative route, starting from 7.Most of the synthesized compounds have been tested for in vitro enzymatic inhibitionactivity. A second goal in this thesis has been to investigate the concept offragment based drug design, based on these inhibition results. Combinations ofpotent substituent groups were found to give target compounds of high potency.The best compound tested gave an IC50-value of 2.4 nM.