Design and Synthesis of Novel Poly ADP-ribose Polymerase 1 (PARP1) Inhibitors for the Treatment of Solid Tumors

Poly ADP-Ribose Polymerase 1 (PARP1) is one of the promising target in cancer biology, specifically for BRCA mutated breast and ovarian cancer. It is a member of ADP-ribosyl transferases (ART) family of enzyme and does post-translational modification of the target protein. PARP1 uses NAD+ as a substrate, cleave it catalytically and transfers the ADP-ribose moiety to acceptor proteins to create long chains of linear and/or branched poly (ADP-ribose) (PAR) as post-translational modification. This is called parylation of the target protein. One of such target proteins is Histone. PARP1 gets up-regulated during DNA damage and it repairs the DNA through involvement of natural Homologous recombination (HR) pathway. Two genes, BRCA1 and BRCA2 are the key components of this pathway and so in cancer patients with BRCA-mutant genes, the HR pathway of DNA repair does not work. So, such patients can be treated with great potential and milder side effects using PARP1 inhibitors based on the synthetic lethality concept. At present, four PARP1 inhibitors; Olaparib, Niraparib, Rucaparib and Talazoparib are approved by USFDA and are in clinical use. All these marketed drugs equally inhibit PARP2 along with PARP1 with almost same potency.