olaparib and Neoplasms

PARP1 plays a crucial role in DNA damage repair, making it an essential target for cancer therapy. PARP1 inhibitors are widely used to treat BRCA-deficient malignancies, and six PARP inhibitors have been approved for clinical use. However, excluding the great clinical success of PARP inhibitors, the concomitant toxicity, drug resistance, and limited scope of application restrict their clinical efficacy. To find solutions to these problems, dual-target inhibitors have shown great potential. In recent years, several studies have linked PAPR1 to other primary cancer targets. Many dual-target inhibitors have been developed using structural fusion, linkage, or library construction methods, overcoming the defects of many single-target inhibitors of PARP1 and achieving great success in clinical cancer therapy. This review summarizes the advance of dual-target PARP1 inhibitors in recent years, focusing on their structural optimization process, structure-activity relationships (SARs), and in vitro or in vivo analysis results.

Topics: DNA Repair; Humans; Neoplasms; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors

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

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that can change the expression of downstream target genes by catalyzing the trimethylation of lysine 27 of histone H3 (H3K27me3). Studies have found that EZH2 is highly expressed in a variety of tumor tissues and is closely related to the occurrence, development, invasion, and metastasis of tumors; therefore, EZH2 is becoming a new molecular target in antitumor therapy. Tazemetostat (EPZ-6438) was approved in 2020 as the first inhibitor targeting catalytic EZH2 for the treatment of epithelioid sarcoma. In addition, a variety of EZH2 inhibitors are being investigated in basic and clinical research for the treatment of tumors, and encouraging results have been obtained. This article systematically reviews the research progress on EZH2 inhibitors and proteolysis targeting chimera (PROTAC)-based EZH2 degradation agents with a focus on their design strategies, structure-activity relationships (SARs), and safety and clinical manifestations.

Topics: Animals; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Hematologic Neoplasms; Histone Methyltransferases; Humans; Molecular Targeted Therapy; Neoplasms; Structure-Activity Relationship

Topics: Cell Line, Tumor; DNA Repair; Humans; Neoplasms; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Humans; Ligands; Mice; Neoplasms; Phthalazines; Piperazines; Poly (ADP-Ribose) Polymerase-1; Proteolysis

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) polymerase-1 (PARP-1) is a new potential target for anticancer drug discovery. A series of bromophenol-thiosemicarbazone hybrids as PARP-1 inhibitors were designed, synthesized, and evaluated for their antitumor activities. Among them, the most promising compound, 11, showed excellent selective PARP-1 inhibitory activity (IC

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; DNA Breaks, Double-Stranded; Drug Discovery; Humans; Hydrogen Peroxide; Inhibitory Concentration 50; Mice; Neoplasms; Phenols; Poly(ADP-ribose) Polymerase Inhibitors; Reactive Oxygen Species; Thiosemicarbazones; 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

We report the antitumor effects of nitric oxide (NO) releasing derivatives of the PARP-1 inhibitor olaparib (1). Compound 5b was prepared by coupling the carboxyl group of 3b and the free amino group of arylated diazeniumdiolated piperazine 4. Analogue 5a has the same structure except that the F is replaced by H. Compound 13 is the same as 5b except that a Me2N-N(O)═NO- group was added para and ortho to the nitro groups of the dinitrophenyl ring. The resulting prodrugs are activated by glutathione in a reaction accelerated by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancers. This metabolism generates NO plus a PARP-1 inhibitor simultaneously, consuming reducing equivalents, leading to DNA damage concomitant with inhibition of DNA repair, and in the case of 13 inducing cross-linking glutathionylation of proteins. Compounds 5b and 13 reduced the growth rates of A549 human lung adenocarcinoma xenografts with no evidence of systemic toxicity.

Topics: Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Proliferation; Comet Assay; DNA Damage; Drug Design; Drug Synergism; Enzyme Inhibitors; Glutathione S-Transferase pi; Humans; Isoenzymes; Models, Molecular; Neoplasms; Nitric Oxide; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Prodrugs; Pyrazines; Structure-Activity Relationship; Xenograft Model Antitumor Assays