Towards Transition-State Inhibitors of 2’-Deoxynucleoside 5’-Phosphate N-Hydrolase 1 (DNPH1)

<p><strong>BRCA1 and BRCA2 are genes that function as tumour suppressors, encoding proteins that are important to the DNA repair process. Individuals who inherit a defective copy of one of these genes have an increased likelihood of developing breast and ovarian cancers.</strong></p><p>Such hereditary breast and ovarian cancers have been successfully treated in recent years with inhibitors of PARP (Poly (ADP-ribose) polymerase). The PARP protein binds to sites of single strand-breaks in DNA and recruits other proteins to repair this damage. Initial optimism over the efficacy of PARP inhibitors has been dampened by the ability of BRCA1/2 deficient cancers to develop resistance to such drugs.</p><p>A promising target for overcoming PARP inhibitor resistance is the nucleotide sanitising enzyme DNPH1. Recent research suggests that drug resistant cancer cells may be re-sensitized to PARP inhibitors, such as Olaparib, if DNPH1 is suppresse Inhibitors of this enzyme have been proposed as combination therapies with approved PARP inhibitors to treat drug resistant BRCA1/2 deficient breast and ovarian cancers. Our group has had great success in making pyrrolidine-derived, enzyme transition-state analogues that have proven to be extremely potent enzyme inhibitors. We anticipated thatsimilar pyrrolidine-derived species will be transition-state analogues for both steps in the DNPH1 reaction mechanism.</p><p>This thesis has established robust strategies for the synthesis of anticipated transition state analogues for both steps in the DNPH1 reaction mechanism. Of these compounds, a series of azasugar derivatives have been established as potent DNPH1 inhibitors by an enzyme inhibition assay. Two compounds from this series (62 and 66) have revealed key SARs with DNPH1 that informed on the design of a best-in-class DNPH1 inhibitor. A prodrug (ProTide 122) form of compound 62 was synthesised and has been proven to sensitise BRCA1 mutant cancer cells to Olaparib.</p>