TIPARP (TCDD Inducible Poly(ADP-Ribose) Polymerase)

High PARP7 expression is associated with estrogen and androgen response, but also with better overall survival and lower cell proliferation.

Provided herein are novel compounds as TIPARP inhibitors, pharmaceutical compositions, use of such compounds in treating head and neck squamous cell carcinoma (HNSCC), and processes for preparing such compounds.

The analysis identified 11 variants affecting both BRCA1 and BRCA2 carriers, most of which increase risk, including the following: IRS1, RSPO1, SYNPO2, BABAM1, MRPL34, PLEKHM1, and TIPARP...The only SNP reaching genome-wide significance (p < 5 × 10-8) was in BNC2. The article summarizes the growing number of genetic modifiers of ovarian cancer risk among BRCA1/2 carriers and highlights their potential to improve individualized risk assessment, enhance patient stratification, support personalized prevention and surveillance strategies, deepen the understanding of disease biology, and identify potential therapeutic targets.

Compared with positive control MRTX849, the synthesized compounds 7g, 7p, 7q, 7r, 7v, and 7y displayed stronger antiproliferative activities against H358 cells with IC50 values of < 1 nM (3D cell culture) and comparable inhibitory potency against KRASG12C...Meaningfully, 7q combined with Nrf2 inhibitor ML385 or PARP7 inhibitor RBN-2397 greatly enhanced the sensitivity of 7q against lung cells (H1373) in vivo. Furthermore, combination therapy of 7q with pan-USP inhibitor PR-619 obtained a statistically significant synergistic inhibition of H1373 cell growth in vitro and in vivo. Our findings indicate that 7q may be a promising drug candidate for the treatment of cancers harboring the KRASG12C mutation, and the results of the combination regimen established a pharmacological foundation for addressing drug resistance.

Compared with parental cells, these resistant cells exhibited reduced sensitivity to paclitaxel, adriamycin, and eribulin in the viability assays. These results suggest that ZSTK3744 combines robust cell growth-inhibitory activity with a favorable safety profile. In conclusion, ZSTK3744 is a promising candidate for overcoming chemotherapy resistance in TNBC, addressing the urgent need for more effective treatment options for this aggressive cancer subtype.

Pathway enrichment analyses highlighted oxidative stress, IL-17, NF-κB, and immune checkpoint signaling. Together, biomass haze-derived PM2.5 from Northern Thailand drives genotype-dependent oxidative stress and transcriptional remodeling in NSCLC cells.

These findings highlight the complexity of the interplay among PARP7, AHR and STING-induced IFN signalling in regulating cancer cell proliferation but also suggest that for some cell lines STING activation might increase their sensitivity to the anti-proliferative effects of RBN2397.

The important functions of PARP7 in liver metabolism, adipogenesis, and antiviral immunity will also be discussed. This systematic review of the multiple roles of PARP7 in developing tumors and other diseases will provide prospects for breakthrough applications of targeting this protein.

Receiver Operating Characteristic (ROC) and Hazard Ratio (HR) analyses demonstrated that the biomarker score was correlated with response to anti-PD-1 therapy in a cohort of kidney cancer patients and correlated with better overall survival (OS) in cancer patients treated with anti-programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapies. In summary, we have identified a transcriptional biomarker that predicts cellular response to PARP7i and AHRa combination therapy which is associated with benefits from immune checkpoint inhibitor (ICI) therapies in cancer patients.

TIPARP is a novel independent prognostic biomarker and potential therapeutic target in pancreatic cancer. It contributes to tumor progression by promoting an immunosuppressive microenvironment and activating pro-tumorigenic signaling. These findings highlight TIPARP as a promising candidate for precision medicine and combination immunotherapy in PAAD.

Notably, ZBP1 loss abrogated these effects, preventing APC recruitment and T cell priming. These findings establish PARP7 and necroptosis as opposing regulators of abscopal responses and nominate PARP7 inhibition as a strategy to overcome RT + ICI resistance.

Notably, the selective PARP7 inhibitor RBN-2397 for tumor treatment has entered Phase II trials, highlighting the translational potential of targeting this enzyme...Furthermore, to advance the study of PARP7 inhibitors, we analyze the mechanisms of action and design strategies of existing PARP7 inhibitors as reported in current papers and patents. Additionally, we share our experiences in designing PARP7 inhibitors and present our insights regarding the opportunities and challenges in this pioneering research field.