PARP1 inhib 
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  • ||||||||||  Helical domain deletion enables discovery of potent PARP1 inhibitors from a DEL selection (Hybrid; Room 353 (Ernest N. Morial Convention Center)) -  Mar 12, 2024 - Abstract #ACSSp2024ACS_Sp_8261;    
    To overcome this, we designed and screened a catalytic domain version of the protein with the autoinhibitory helical domain deleted with a DEL collection of ~5 billion members. This allowed us to interrogate a functionally relevant form of the protein to discover novel indole-containing PARP1 inhibitors, with single digit nanomolar potency, which we would not have discovered by simply screening the native catalytic domain.
  • ||||||||||  HSK39775 / Haisco
    HSK39775: A USP1 inhibitor for the treatment of cancers with homologous recombination deficiencies (Section 23) -  Mar 5, 2024 - Abstract #AACR2024AACR_9418;    
    Interestingly, HSK39775 inhibited the tumor growth of a HRP and BRCA wild-type lung cancer xenograft as a single agent with TGI of 94% at 30 mg/kg QD, suggesting the therapeutic effect of USP1 inhibitors beyond canonical BRCA mutant or HRD tumors. In summary, these results indicate HSK39775 as a potent and selective USP1 inhibitor and support further development.
  • ||||||||||  Lynparza (olaparib) / Merck (MSD), AstraZeneca
    Quantitative proteomics reveal the mechanism of TTFields therapy for glioblastoma (Section 20) -  Mar 5, 2024 - Abstract #AACR2024AACR_9062;    
    Based on this analysis, we hypothesized that combining TTFields with Olaparib (a PARP1 inhibitor) might enhance the sensitivity of TTFields...Under TTFields intervention, the expression of PARP1 was upregulated, and the use of a PARP1 inhibitor in combination significantly increased the sensitivity of TTFields. Therefore, this study not only elucidated the molecular mechanisms of TTFields therapy for GBM treatment at the systems biology level, but also provided support for further enhancing the efficacy of TTFields.
  • ||||||||||  Lenvima (lenvatinib) / Eisai, Merck (MSD), Rubraca (rucaparib) / Pharma& Schweiz
    Identification of serine/threonine kinase 39 (STK39) as a driver for multidrug resistance in hepatocellular carcinoma (Section 8) -  Mar 5, 2024 - Abstract #AACR2024AACR_8628;    
    Additionally, STK39 plays a critical role in regulating PARP1-mediated chromatin decondensation, which enables it to open chromatin structure at the promoter regions of SOX2/OCT4. In summary, treatment of molecular targeted drugs including rucaparib and lenvatinib with STK39 inhibitor may be a potential therapeutic strategy for treatment of this deadly disease.
  • ||||||||||  HSK40495 / Haisco
    HSK40495, a highly selective PARP1 inhibitor with improved hematopoietic safety for the treatment of HRD cancers (Section 22) -  Mar 5, 2024 - Abstract #AACR2024AACR_6871;    
    In summary, HSK40495, a highly selective PARP1inhibitor over other PARP family members, exhibits excellent pharmacological and safety properties, and also has the favorable pharmacokinetics profile in preclinical studies. All these findings suggest that HSK40495 has the great potential to be a promising PARP1 inhibitor for further development in the patients with HRD tumors.
  • ||||||||||  ACE-86225106 / Acerand Therap
    Discovery of a highly potent and selective PARP1 inhibitor with superior PK and safety profiles (Section 22) -  Mar 5, 2024 - Abstract #AACR2024AACR_6862;    
    Taken together, ACE-86225106 is a highly potent, selective PARP1 inhibitor with excellent PK and safety profile and expected to have a better safety profile, deeper and more durable clinical responses, and broader utility in the clinic as a preferred combination partner with other anti-cancer therapies. A phase 1 clinical trial to evaluate its safety, PK, and clinical utility is to begin in early 2024.
  • ||||||||||  saruparib (AZD5305) / AstraZeneca, Talzenna (talazoparib) / Pfizer, Lynparza (olaparib) / Merck (MSD), AstraZeneca
    Measuring cellular PARylation to gain insight in PARP / PARG-targeted drug discovery (Section 28) -  Mar 5, 2024 - Abstract #AACR2024AACR_6749;    
    A phase 1 clinical trial to evaluate its safety, PK, and clinical utility is to begin in early 2024. 2) Titration of the three PARP1/2 inhibitors Talazoparib, Olaparib and AZD5305, in combination with a DNA damage agent and PDD00017273 inhibitor, shows a dose-dependent reduction in cellular PARylation in HEK293 cells, as expected since PARP1 is activated in response to DNA damage and this activation is blocked by the inhibitors (IC50 values, Olaparib = 0.013
  • ||||||||||  SNV-001 / Synnovation Therap
    Activity of PARP1-selective inhibitor SNV-001 in models of HRD cancers as monotherapy and in combination (Section 23) -  Mar 5, 2024 - Abstract #AACR2024AACR_6718;    
    Combination of SNV-001 with polymerase theta inhibitor ART558 or USP1 inhibitor KSQ4279 exhibited synergistic effects in DLD1 (BRCA2 -/-) or UWB1.289 (BRCA1mut) cells...Current data highlight a potential strategy for improving treatment efficacy and overcoming resistance. Further clinical investigations are warranted to validate this combination strategy.
  • ||||||||||  Advancing precision oncology: Insights from pan-cancer proteogenomic signatures (Section 41) -  Mar 5, 2024 - Abstract #AACR2024AACR_6621;    
    In summary, our identification of expression signatures facilitates phenotype prediction and unveils their molecular mechanisms. We anticipate clinical utility in classifying samples using proteogenomics, particularly in cases where a solely genomic assessment is inconclusive.
  • ||||||||||  Cancer metabolism in radiation resistance: Complementary roles of O-GlcNAc transferase and PARP1 (Section 12) -  Mar 5, 2024 - Abstract #AACR2024AACR_5943;    
    Driving hyperresection by targeting O-GlcNAcylation or H3K27 trimethylation along with PARP inhibition may saturate the capacity of HR and produce irreversible damage in cancer cells. Targeting impacts of metabolic reprogramming on DSB repair may not only enhance the therapeutic index of radiation but also sharpen synthetic lethality with HR deficiency.
  • ||||||||||  veliparib (ABT-888) / AbbVie
    Senescent cancer cell vaccines induce cytotoxic T cell responses targeting primary tumors and disseminated tumor cells (Section 15) -  Mar 5, 2024 - Abstract #AACR2024AACR_5632;    
    We have explored the potential for SnCs to serve as vaccines, building upon prior findings where we demonstrated the immunogenic senescence triggered by the combination of ionizing radiation (IR) and the PARP1/2 inhibitor veliparib...They not only confer protective immunity against tumor engraftment but also act as therapeutic vaccines, inhibiting both primary and disseminated tumor growth, and synergize with radiotherapy and immune checkpoint blockade. While direct administration of tumor-derived SnCs to patients may raise safety concerns, pulsing autologous DCs with tumor SnCs may help drive anti-tumor immune response, offering a promising path toward personalized cancer immunotherapy.
  • ||||||||||  HH102007 / HaiHe Biopharma
    HH102007 is a highly selective and potent PARP1 inhibitor and trapper (Section 52) -  Mar 5, 2024 - Abstract #AACR2024AACR_2140;    
    Given the availability of potent and non-toxic PDE4D inhibitors, and clinically approved EGFR and PARP1 inhibitors, our findings have great translational potential to improve the clinical outcome of refractory ER+ breast cancers. Abstract is embargoed at this time.
  • ||||||||||  Lynparza (olaparib) / Merck (MSD), AstraZeneca, Zejula (niraparib) / GSK, J&J
    Review, Journal, PARP Biomarker:  A review of poly(ADP-ribose)polymerase-1 (PARP1) role and its inhibitors bearing pyrazole or indazole core for cancer therapy. (Pubmed Central) -  Mar 4, 2024   
    Therefore, this review aims to address the importance of PARP1 in cell regulation and its role in cancer. Moreover, it intends to report a comprehensive literature review of PARP1 inhibitors, containing the pyrazole and indazole scaffolds, published in the last fifteen years, focusing on structure-activity relationship aspects, thus providing important insights for the design of novel and more effective PARP1 inhibitors.
  • ||||||||||  Journal:  ChemMORT: an automatic ADMET optimization platform using deep learning and multi-objective particle swarm optimization. (Pubmed Central) -  Feb 22, 2024   
    Based on reversible molecular representation and particle swarm optimization strategy, the Molecular Optimizer can be used to effectively optimize undesirable ADMET properties without the loss of bioactivity, which essentially accomplishes the design of inverse QSAR. The constrained multi-objective optimization of the poly (ADP-ribose) polymerase-1 inhibitor is provided as the case to explore the utility of ChemMORT.
  • ||||||||||  Journal:  Novel PARP1 Inhibitors for Treating Cancer. (Pubmed Central) -  Feb 14, 2024   
    Trial completion date: Dec 2023 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Jun 2025 Provided herein are novel PARP1 inhibitors, their pharmaceutical compositions, the use of such compounds in treating cancer, and processes for preparing such compounds.
  • ||||||||||  ED13- New Targets and Mechanisms of Synthetic Lethality in Cancer Therapy (Room 11 - Upper Level - Convention Center) -  Feb 5, 2024 - Abstract #AACR2024AACR_349;    
    The third talk by Zev A Wainberg will explore the efforts to develop WRN inhibitors for the treatment of mismatch repair deficient cancers. WRN inhibitors being developed by Novartis and Vividion/Roche are entering clinical trials.
  • ||||||||||  Preclinical, Journal:  Design of Two New Sulfur Derivatives of Perezone: In Silico Study Simulation Targeting PARP-1 and In Vitro Study Validation Using Cancer Cell Lines. (Pubmed Central) -  Jan 27, 2024   
    Additionally, theoretical calculations were carried out using the density functional theory (DFT) with the hybrid method B3LYP with a set of base functions 6-311++G(d,p), and the reactivity properties were compared between the natural derivatives of perezone and the three synthesized compounds, and the obtained results exhibited that 9 has the best properties to bind with PARP-1. Finally, it is important to mention that 9 displays significant inhibitory activity against MDA-MB-231 and MCF-7 cells, i.e., 145.01 and 83.17