rucaparib and Neoplasms

DDR (DNA damage response) defects in cells drive tumor formation by promoting DNA mutations, which also provides cancer-specific vulnerabilities that can be targeted by synthetic lethality-based therapies. Until now, PARP inhibitors like olaparib are the first successful case of utilizing synthetic lethality-based therapy to treat cancers with DNA-repairing deficiency (e.g. BRCA1 or BRCA2 mutation), which has fueled the search for more targetable components in the DDR signaling pathway by exploiting synthetic lethality, including but not limited to DNA-PK, ATR, ATM, CHK1, and WEE1. After years of efforts, numerous DDR kinase inhibitors have been discovered. Some of them are being investigated in clinical trials and have shown promising results for cancer therapy. In this review, we summarize the latest advancement in the development of DDR kinase inhibitors including those in preclinical stages and clinical trials, the crystal structures of DDR enzymes, and binding modes of inhibitors with target proteins. The biological functions involving different genes and proteins (ATR, DNA-PK, ATM, PARP, CHK1, and WEE1) are also elucidated.

Topics: DNA Damage; DNA Repair; Humans; Mutation; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Signal Transduction

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.

Topics: Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Survival; Half-Life; Humans; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Naphthyridines; Neoplasms; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Quinolones; Structure-Activity Relationship; Transplantation, Heterologous

Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290,

Topics: Animals; Binding Sites; Carbazoles; Cell Proliferation; Dogs; Female; Fluorenes; Half-Life; Humans; Indoles; Isoenzymes; Mice; Microsomes; Molecular Docking Simulation; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Rats; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Poly(ADP-ribose) polymerases (PARPs) are involved in DNA repair following damage by endogenous or exogenous processes. It has become clear over the past decade that inhibition of PARP in the context of defects in other DNA repair mechanisms provide a tumor specific way to kill cancer cells. We describe the rationale for this approach and the design and discovery of niraparib, a potent PARP-1/2 inhibitor with good cell based activity, selectivity for cancer over normal cells, and oral bioavailability. Niraparib was characterized in a number of preclinical models before moving to phase I clinical trials, where it showed excellent human pharmacokinetics suitable for once a day oral dosing, achieved its pharmacodynamic target for PARP inhibition, and had promising activity in cancer patients. It is currently being tested in phase 3 clinical trials as maintenance therapy in ovarian cancer and as a treatment for breast cancer.

Topics: Animals; BRCA1 Protein; BRCA2 Protein; Drug Discovery; Enzyme Inhibitors; Homologous Recombination; Humans; Indazoles; Models, Molecular; Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases