RP6685 / XenoTherapeutics - LARVOL DELTA

The emerging landscape of polymerase θ in tumor pathogenesis and precision treatment. (PubMed, Biochem Biophys Res Commun) - "The review also provides a critical evaluation of current Polθ inhibitors-including ART558, RP-6685, novobiocin, and AB25583-focusing on their mechanisms, synthetic lethality profiles, and ability to overcome PARP inhibitor resistance. By bridging molecular mechanisms with tumor biology and therapeutic translation, this review offers a unique framework for understanding Polθ as both a prognostic biomarker and a precision oncology target, with implications for combination therapies involving radiotherapy, immunotherapy, and chemotherapy."

IO biomarker • Journal • Review • Breast Cancer • Colorectal Cancer • Gene Therapies • Immune Modulation • Immunology • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • POLQ • RAD51

Polymerase θ (POLθ) inhibitors (novobiocin, ART-558, RP6685) were tested with 22 approved and investigational agents in multi-cell type spheroids of genetically selected patient-derived human tumor cell lines (AACR 2024) - "The potential of novobiocin to augment cancer chemotherapy was explored in the late 1980s and early 1990s in tumor cells and tumor-bearing mice and in Phase 1 clinical trials with cyclophosphamide or cisplatin...Potentiation of the topoisomerase II inhibitors doxorubicin (DOX) and etoposide by the POLθ inhibitors ART-558 or RP6685 was observed in spheroids grown from the serous endometrial adenocarcinoma 922993-354-T-J3, which has ATM and BRCA2 variants...Activity of the Chk1/2 inhibitor prexasertib was potentiated by either ART-558 or RP6685 in the 922993-354-T-J3 complex spheroids...KRAS G12D inhibitor MRTX-133 cytotoxicity against 186277-243-T-J2 colon adenocarcinoma with the KRAS G12D variant was potentiated by either ART-558 or RP6685. Potential combinations to advance into in vivo studies will be presented."

Late-breaking abstract • Preclinical • Tumor cell • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Endometrial Adenocarcinoma • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRCA • BRCA2 • KRAS • LIG3 • PALB2 • POLQ • XRCC1

Discovery of 1-(arylacetyl)-2-phenyl-pyrrolidine Derivatives as Novel POLθ-pol Inhibitors via Structure-Based Virtual Screening and Fragment Fusion. (PubMed, Drug Dev Res) - "The followed similarity research obtained a more potent analogue SS-5, which was hybridized with RP-6685 to get 1-(phenylacetyl)-2-phenyl-pyrrolidine derivative F-1. It showed potent POLθ inhibitory activity with an IC50 value of 170 nM, and good anti-proliferative activity against BRCA2-deficient DLD1 and HCT116 cell lines, with IC50 values of 4.39 μM and 4.79 μM, respectively. Further MD simulations and interaction analysis disclosed the possible binding mode of F-1 with POLθ-pol."

Journal • Oncology • BRCA • BRCA2 • POLQ

Polymerase Ѳ inhibitors combinations with approved and investigational agents in patient-derived tumor multi-cell type (mct) spheroids. (PubMed, Exp Mol Pathol) - "The potential of novobiocin, recently identified to be a DNA POLѲ inhibitor, to augment cancer chemotherapy was explored in the late 1980s and early 1990s in tumor cells, tumor-bearing mice and in Phase 1 clinical trial in combination with cyclophosphamide or cisplatin...In simultaneous combination with ART-558, talazoparib produced greater-than-additive cytotoxicity at the highest concentrations of the POLѲ inhibitors in the 922,993-354-T-J3-PDC endometrial serous carcinoma mct-spheroids. Activity of the Chk1/2 inhibitor prexasertib was potentiated by either ART-558 or RP6685 in the 922,993-354-T-J3 mct-spheroids...Regions of potentiation were evident in the 922,993-354-T-J3-PDC endometrial carcinoma survival surface plots at the highest concentration of paclitaxel tested, while regions of potentiation were evident in the paclitaxel mid-concentrations of the 299,254-011-R-J1-PDC melanoma mct-spheroids survival surface plots as determined by the Bliss independence..."

Journal • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Endometrial Serous Carcinoma • Melanoma • Oncology • Solid Tumor • BRCA • LIG3 • MSI • PALB2 • PARP1 • XRCC1