M9831 / EMD Serono, Vertex - LARVOL DELTA

Targeting DNA-PK: medicinal chemistry insights into small-molecule inhibitor discovery and optimisation. (PubMed, RSC Med Chem) - "Representative scaffolds, including chromen-4-one derivatives and next-generation clinical candidates such as AZD7648 and VX-984, are discussed. Finally, we summarise current clinical progress in early phase trials and remaining challenges, including achieving tolerability and efficacy when compounds are administered both as a single agent, or in combination. Taken together, this review highlights both the therapeutic potential of DNA-PK-targeting inhibition and the challenges encountered in clinical development, providing a framework to guide future strategies for DNA-PK-targeted therapeutics."

Journal • Review • Oncology

Oncolytic HSV Synergizes with DNA-PKcs Inhibition to Abrogate Stemness and DNA Repair in Glioblastoma (ASGCT 2026) - "DNA-PKcs pharmacological inhibitors included NU7441, AZD7648, VX-984, and predominantly M3814 (Peposertib), a selective, brain-penetrant inhibitor currently in clinical trial...GSCs transduced with doxycycline-inducible DNA-PKcs shRNA were used to validate selectivity...Integrating DDR inhibition with oHSV therapy simultaneously attacked stemness and DNA repair, two critical survival pathways, offering a novel synthetic lethal-like approach. These results warrant further clinical investigation of oHSV and DNA-PKcs inhibitors in GBM and potentially other solid tumors."

Brain Cancer • Glioblastoma • Herpes Simplex • Infectious Disease • Solid Tumor • MYC • SOX2

Deuteration of Six-Membered N-Heteroarenes: Chemistry and Applications. (PubMed, Chemistry) - "For example, VV116 and VX-984, approved therapeutics for the treatment of COVID-19 and cancer, and deuterated functional materials for use as ligands in catalysts and organometallic light-emitters...In this work, we comprehensively review approaches developed for the incorporation of D into 6NHetAr, their fused counterparts, and complex compounds containing 6NHetAr. We also provide an overview of established and emerging applications for these materials."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Oncology

Hyperglycemia-induced DNA damage response activates DNA-PK complex to promote endothelial ferroptosis in type 2 diabetic cardiomyopathy. (PubMed, Theranostics) - "Key DDR and ferroptosis markers were validated in cardiac microvascular endothelial cells (CMECs) isolated from mice with streptozotocin (STZ)/high-fat diet (HFD)-induced T2DM, with and without treatment with the DNA-PK inhibitors NU7441 or M9831. Our findings implicate the DNA-PK complex as a key regulator of hyperglycemia-induced endothelial ferroptosis in T2DM cardiomyopathy. Targeting DNA-PK complex may represent a novel therapeutic strategy for mitigating microvascular dysfunction and cardiac decline in T2DM."

Journal • Cardiomyopathy • Cardiovascular • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • ACSL4 • GPX4 • PACERR • PRKDC • PTGS2 • SLC7A11 • XRCC5 • XRCC6

Cell Context is the third axis of synergy for the combination of ATR inhibition and cisplatin in Ewing sarcoma. (PubMed, Clin Cancer Res) - "These data exploit EWS-FLI1 driven alterations in cell context to broaden the therapeutic window of berzosertib and cisplatin to establish a promising combination therapy and a novel in vivo schedule."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • CHEK1 • EWSR1 • FLI1

Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs. (PubMed, Cancer Res Commun) - "The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein; berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase; nedisertib or VX-984). The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations."

Combination therapy • Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • ATR

[VIRTUAL] Combination screening of DNA damaging agents temozolomide and trabectedin with inhibitors of DNA repair using a complex spheroid model with a panel of patient-derived and established tumor cell lines (AACR 2021) - "The spheroids were treated with temozolomide or trabectedin as single agents or in combination with a PARP inhibitor (olaparib or talazoparib), an ATM inhibitor (AZD-1390), an ATR inhibitor (berzosertib (M6620) or BAY-1895344), a DNA-PK inhibitor (nedisertib (M3814) or VX984) or a BET bromodomain inhibitor (birabresib). Overall, greater than additive responses were observed more frequently with trabectedin combinations containing the ATM inhibitor AZD-1390 or the DNA-PK inhibitor nedisertib, as well as temozolomide combinations with the PARP inhibitors olaparib or talazoparib or the ATR inhibitor BAY-1895344, particularly among sarcoma and small cell lung cancer models. These results might inform the prioritization of drug combinations for further investigation."

Preclinical • Lung Cancer • Neuroendocrine Tumor • Oncology • Sarcoma • Small Cell Lung Cancer • Solid Tumor

[VIRTUAL] DNA damage inhibitors with topotecan in a complex spheroid model in PDM and established cell lines (AACR-II 2020) - "The response to topotecan was determined over a concentration range achievable in patients alone and in combination with nedisertib (M3814) or VX984, DNA PK inhibitors, M6620 or BAY-1895344, ATR inhibitors, MK-1775, a Wee-1 inhibitor, AZD-1390, an ATM inhibitor or olaparib or talazoparib, PARP inhibitors. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E."

Preclinical • Ewing Sarcoma • Lung Cancer • Oncology • Rhabdomyosarcoma • Sarcoma • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Thoracic Cancer

The DNA-PK inhibitor VX-984 enhances the radiosensitivity of glioblastoma cells grown in vitro and as orthotopic xenografts. (PubMed, Mol Cancer Ther) - "The survival of mice receiving the combination protocol was significantly increased as compared with control and as compared with radiation alone. These results indicate that VX-984 enhances the radiosensitivity of brain tumor xenografts and suggest that it may be of benefit in the therapeutic management of GBM."

Journal • Preclinical