Design, synthesis and evaluation of PKD inhibitors for cancer treatment

Cancer is gradually becoming the leading cause of premature death in our global society. In Europe, approximately one in three develops cancer before the age of 75. With a global death rate of almost 10 million individuals per year, there is a clear need for better treatments. This thesis aimed at developing novel and potent small molecule inhibitors of Protein Kinase D (PKD), an attractive anti-cancer drug target. In first instance, novel pyrazolo[3,4-d]pyrimidine-based pan-PKD inhibitors with structural variety at position 1 were synthesized and evaluated for biological activity. Starting from in-house discovered lead 3-IN-PP1, compound 2.17m was identified with an improved biochemical inhibitory activity against PKD (IC50 = 17-35 nM). Subsequent cellular assays demonstrated that 3-IN-PP1 and 2.17m inhibited PKD-dependent cortactin phosphorylation. Finally, a screening against different cancer cell lines demonstrated that 3-IN-PP1 shows potent antitumor activity. Although some of the currently known PKD inhibitors show good potency in several cancer models, they all inhibit the three PKD isoforms to the same extent. However, recent research showed that these isoforms have differential roles depending on the cancer type. PKD1 is in general more associated with tumor-suppressive functions while PKD2 and 3 drive tumor formation. Therefore, the second part is devoted towards the development of PKD2/3 selective inhibitors. A virtual screening approach coupled to synthetic optimization resulted in several weak inhibitors with selectivity for PKD2 over PKD1/3. Finally, novel synthetic methodology was developed for the synthesis of biologically relevant N-acyl sulfamates. Fluorosulfates, an emerging class of electrophiles, were used to construct these sulfamates precluding the need of chlorosulfonyl isocyanate and sulfamoyl chloride. In combination with amides, a wide and diverse set of N-acyl sulfamates was synthesized, including functionalized bioactive compounds. Several analogues have been tested for activity in a broad antitumor screening.

Publication year:2020

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