olaparib and Triple-Negative-Breast-Neoplasms

The therapeutic strategy of poly (ADP-ribose) polymerase (PARP) inhibition of BRCA1/2 mutant cancers has been overwhelmingly successful, however, the highly aggressive triple negative breast cancers (TNBC) that receptor protein tyrosine kinase (RTKs) is known to be overexpressed are not sensitive to PARP inhibitors. Our research focused on exploring PARP inhibitors incorporating a bicyclic tetrahydropyridine pyrimidine. All synthesized compounds were more potent than Olaparib (ola) in killing tumor cells, especially in TNBC. Furthermore, compound 7 exhibited strong inhibitory effects on PARP enzymatic activity, moreover, the expression of EGFR and phosphorylated EGFR was inhibited by compound 7. Therefore, compound 7 can effectively inhibit TNBC cells with high expression of EGFR. In addition, significant synergistic effect of anti-tumor effect of new PARP inhibitors and adriamycin was also observed.

Topics: BRCA1 Protein; Cell Line, Tumor; ErbB Receptors; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Triple Negative Breast Neoplasms

Triple negative breast cancer (TNBC) is a complex and heterogeneous neoplasm, and till now no effective therapies are available. PARP inhibitors, which target DNA repair, are lethal to those cells that have impaired homologous recombination (HR) pathway. So, PARP inhibitors might exert promising results in the treatment of BRCA-mutated TNBC, but show compromised effect to those wild-type TNBC. Herein, we describe a novel PROTACs C8, which was obtained by conjugating PARP1/2 inhibitor Olaparib to KB02, can induce potent and specific degradation of PARP2 by recruiting DCAF16 E3 ligase for treatment of wild-type TNBC. Moreover, C8 exhibits therapeutic potential in TNBC cell lines MDA-MB-231 both in vitro and in vivo. These studies demonstrated that the DCAF16 E3 ligases can be used in PARP2 PROTACs design, and C8, as a novel PARP2 selective DCAF16 based PROTACs, might be a promising lead compound for the treatment of BRCA-wild-type TNBC.

Topics: Cell Line, Tumor; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Triple Negative Breast Neoplasms; Ubiquitin-Protein Ligases

The effective potency and resistance of poly(ADP-ribose) polymerase (PARP) inhibitors limit their application. Here, we exploit a new paradigm that mimics the effects of breast cancer susceptibility genes (BRCA) mutations to trigger the possibility of synthetic lethality, based on the previous discovery of a potential synthetic lethality effect between bromodomain-containing protein 4 (BRD4) and PARP1. Consequently, the present study describes compound

Topics: Antineoplastic Agents; BRCA1 Protein; Cell Cycle Proteins; Cell Line, Tumor; Homologous Recombination; Humans; Nuclear Proteins; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Quinazolinones; Synthetic Lethal Mutations; Transcription Factors; Triple Negative Breast Neoplasms

Poly (ADP-ribose) polymerase (PARP) inhibitors show potent antiproliferative activity in treatment with triple-negative breast cancer (TNBC) when combined with chemotherapeutic drugs. However, the emergence of safety issues and drug-resistance of PARP inhibitors prompt us to search for new strategies. It was proved that Proteolysis Targeting Chimeras (PROTACs) is more effective than traditional small molecule which can induce target proteins degradation rather than inhibition. In this article, based on the Olaparib derivatives and cereblon (CRBN) E3 ligase ligands, a series of PARP1 degraders, with linkers bearing different length and type were designed and synthesized. Among them, compound LB23 showed efficacious antiproliferative activity in various human cancer cells and can induce PARP1 protein degradation effectively. Moreover, LB23 showed 60-fold degradation selectivity in tumor cells with low degradation toxicity in normal cells. This study shows that the PROTAC tumor selectivity can be optimized by tuning the length and composition of the linker.

Topics: Cell Line, Tumor; Humans; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Proteolysis; Triple Negative Breast Neoplasms; Ubiquitin-Protein Ligases

Co-targeting PARP and PI3K by PARP/PI3K dual inhibitors has been recognized as a promising chemotherapeutic strategy for the treatment of triple negative breast cancer (TNBC) in our previous work. To further explore novel and more potent PARP/PI3K dual inhibitors, a series of compounds were designed, synthesized and evaluated for their pharmacological properties, resulting in the candidate compound 12, a potent and highly selective PARP/PI3K dual inhibitor. Compared to Olaparib, compound 12 exhibits a superior antiproliferative profile against BRCA-proficient MDA-MB-468 cells. In MDA-MB-468 cell-derived xenograft model, compound 12 displayed excellent antitumor efficacy at a dose of 50 mg/kg, which is considerably more efficacious than the single administration of Olaparib or BKM120. Furthermore, compound 12 displayed good metabolic stability and high safety. Taken together, these results suggest that compound 12 as a novel PARP/PI3K dual inhibitor is worthy for further study.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Male; Mice; Mice, Inbred BALB C; Models, Molecular; Molecular Docking Simulation; Molecular Targeted Therapy; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Protein Binding; Solubility; Structure-Activity Relationship; Triple Negative Breast Neoplasms

Triple-negative breast cancer (TNBC) has an aggressive phenotype and poor prognosis due to the lack of specific targeted treatments. The development of an effective therapeutic strategy with a novel mechanism is essential for TNBC management. Olaparib, a PARP inhibitor, has been approved for the treatment of breast or ovarian cancer patients with breast cancer gene 1/2 (BRCA1/2) mutations. Here, we report the development of a small molecule targeting PARP1 based on the hydrophobic tagging (HyT) method. Targeted protein misfolding and consequent degradation are caused by HyT. Hydrophobic-tagged olaparib induces the proteasome-dependent degradation of PARP1 and shows enhanced antitumor effects compared to olaparib in TNBC cells. In addition, hydrophobic-tagged olaparib causes ER stress-related unfolded protein response (UPR), autophagy, and apoptosis. These results point towards encouraging prospects for chemically modifying approved drugs that not only exhibit superior effects compared to those of the original drugs by triggering novel mechanisms but also provide great feasibility in the translational scenario.

Topics: Antineoplastic Agents; Apoptosis; Female; Humans; Hydrophobic and Hydrophilic Interactions; Phthalazines; Piperazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Proteasome Endopeptidase Complex; Proteolysis; Triple Negative Breast Neoplasms; Unfolded Protein Response

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Autophagy-Related Protein-1 Homolog; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Drug Synergism; Female; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins; Mice, Inbred C57BL; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrimidines; Triple Negative Breast Neoplasms

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Cell Proliferation; Dacarbazine; Drug Screening Assays, Antitumor; Female; Heterografts; High-Throughput Screening Assays; Humans; Isoindoles; Mice, Inbred BALB C; Mice, Nude; Microsomes, Liver; Models, Molecular; Neoplasm Transplantation; Pancreatic Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Rats, Sprague-Dawley; Structure-Activity Relationship; Temozolomide; Triple Negative Breast Neoplasms