NERx 329 is a replication protein A ( RPA ) inhibitor with an IC50 of 4.9 μM. NERx 329 blocks the interaction between RPA and single-stranded DNA, and induces functional RPA depletion, loss of single-stranded DNA gap protection, chromosome fragmentation and cell death. NERx 329 inhibits the DNA damage response signaling pathway, exhibits broad single-agent anticancer activity, and enhances the activity of DNA-damaging agents. NERx 329 can be used in research related to brca1-deficient breast cancer, non-small cell lung cancer, and brca1-deficient ovarian cancer [1] [2].
In Vivo, NERx 329 (25 mg/kg; i.p.; once daily) exhibits significant single-agent anticancer activity in BRCA1-deficient triple-negative breast cancer xenografts, and combination treatment with Olaparib completely abrogates tumor growth without increased toxicity[2].
In Vitro, NERx 329 (Compound 43) exhibits significantly enhanced relative cellular uptake in H460 non-small cell lung cancer cells[1]. NERx-329 (4.3-7.2 μM; 5 d) inhibits the proliferation of A549 non-small cell lung cancer cells in a dose-dependent manner, and its antiproliferative effect is enhanced when combined with Cisplatin [2]. NERx-329 (30 μM; 2 h) slows the replication fork speed in A549 non-small cell lung cancer cells, but does not alter the replication fork speed in BRCA1-deficient triple-negative breast cancer cells MDA-MB-436[2]. NERx-329 (30 μM; 1 h) impairs replication fork restart in A549 non-small cell lung cancer cells and MDA-MB-436 BRCA1-deficient triple-negative breast cancer cells[2]. NERx-329 (2-5 μM; 7-10 d) inhibits the proliferation of BRCA1-deficient triple-negative breast cancer cell line MDA-MB-436. Combined use with Olaparib induces cell death, and repeated administration maintains its antiproliferative activity[2]. NERx-329 (30 μM; 3 h) combined with Olaparib depletes RPA protection in MDA-MB-436 BRCA1-deficient triple-negative breast cancer cells, thereby triggering MRE11-dependent degradation of PARPi-induced single-stranded DNA (ssDNA) gaps[2]. NERx-329 (30 μM; 2 h) combined with Olaparib increases the formation of double-stranded DNA breaks in MDA-MB-436 BRCA1-deficient triple-negative breast cancer (TNBC) cells[2]. NERx-329 (5-10 μM; 3 d) combined with Olaparib induces extensive chromosome shattering in MDA-MB-436 BRCA1-deficient triple-negative breast cancer cells, increasing the proportion of shattered chromosomes to approximately 19%[2]. NERx-329 (2-3 μM; 5 days) combined with the PARP1-specific inhibitor Saruparib induces cell death in MDA-MB-436 BRCA1-deficient triple-negative breast cancer cells, suppresses proliferation recovery of UWB1.289 BRCA1-deficient ovarian cancer cells, and enhances antiproliferative efficacy in BRCA1-complemented UWB1.289 ovarian cancer cells[2]. NERx-329 (3-6 μM; 48-120 h) induces dose-dependent G1-phase and S-G2-M-phase arrest as well as mitotic escape in MDA-MB-436 BRCA1-deficient triple-negative breast cancer cells and A549 non-small cell lung cancer cells, and no additional cell cycle effects occur when combined with PARP inhibitors[2].
References:
[1]. Gavande NS, et al. Structure-Guided Optimization of Replication Protein A (RPA)-DNA Interaction Inhibitors. ACS Med Chem Lett. 2020;11(6):1118-1124. Published 2020 Jan 2.
[2]. VanderVere-Carozza PS, et al. Replication protein A protects lagging strand gaps, restricting PARP inhibitor-induced synthetic lethality in BRCA1-deficient tumors. Nucleic Acids Res. 2026;54(8):gkag396.
In Vivo, NERx 329 (25 mg/kg; i.p.; once daily) exhibits significant single-agent anticancer activity in BRCA1-deficient triple-negative breast cancer xenografts, and combination treatment with Olaparib completely abrogates tumor growth without increased toxicity[2].
In Vitro, NERx 329 (Compound 43) exhibits significantly enhanced relative cellular uptake in H460 non-small cell lung cancer cells[1]. NERx-329 (4.3-7.2 μM; 5 d) inhibits the proliferation of A549 non-small cell lung cancer cells in a dose-dependent manner, and its antiproliferative effect is enhanced when combined with Cisplatin [2]. NERx-329 (30 μM; 2 h) slows the replication fork speed in A549 non-small cell lung cancer cells, but does not alter the replication fork speed in BRCA1-deficient triple-negative breast cancer cells MDA-MB-436[2]. NERx-329 (30 μM; 1 h) impairs replication fork restart in A549 non-small cell lung cancer cells and MDA-MB-436 BRCA1-deficient triple-negative breast cancer cells[2]. NERx-329 (2-5 μM; 7-10 d) inhibits the proliferation of BRCA1-deficient triple-negative breast cancer cell line MDA-MB-436. Combined use with Olaparib induces cell death, and repeated administration maintains its antiproliferative activity[2]. NERx-329 (30 μM; 3 h) combined with Olaparib depletes RPA protection in MDA-MB-436 BRCA1-deficient triple-negative breast cancer cells, thereby triggering MRE11-dependent degradation of PARPi-induced single-stranded DNA (ssDNA) gaps[2]. NERx-329 (30 μM; 2 h) combined with Olaparib increases the formation of double-stranded DNA breaks in MDA-MB-436 BRCA1-deficient triple-negative breast cancer (TNBC) cells[2]. NERx-329 (5-10 μM; 3 d) combined with Olaparib induces extensive chromosome shattering in MDA-MB-436 BRCA1-deficient triple-negative breast cancer cells, increasing the proportion of shattered chromosomes to approximately 19%[2]. NERx-329 (2-3 μM; 5 days) combined with the PARP1-specific inhibitor Saruparib induces cell death in MDA-MB-436 BRCA1-deficient triple-negative breast cancer cells, suppresses proliferation recovery of UWB1.289 BRCA1-deficient ovarian cancer cells, and enhances antiproliferative efficacy in BRCA1-complemented UWB1.289 ovarian cancer cells[2]. NERx-329 (3-6 μM; 48-120 h) induces dose-dependent G1-phase and S-G2-M-phase arrest as well as mitotic escape in MDA-MB-436 BRCA1-deficient triple-negative breast cancer cells and A549 non-small cell lung cancer cells, and no additional cell cycle effects occur when combined with PARP inhibitors[2].
References:
[1]. Gavande NS, et al. Structure-Guided Optimization of Replication Protein A (RPA)-DNA Interaction Inhibitors. ACS Med Chem Lett. 2020;11(6):1118-1124. Published 2020 Jan 2.
[2]. VanderVere-Carozza PS, et al. Replication protein A protects lagging strand gaps, restricting PARP inhibitor-induced synthetic lethality in BRCA1-deficient tumors. Nucleic Acids Res. 2026;54(8):gkag396.