DDO3602 is a PARP1 HSPTAC ( HSP90 -mediated proteolysis-targeting chimera) degrader, with a DC50 of 490.3 nM against PARP1; its K d values for PARP1 and HSP90 are 66.5 nM and 1.64 nM, respectively. DDO3602 induces the formation of an unnatural PARP1-HSP90 ternary complex, recruits E3 ubiquitin ligase, and promotes PARP1 degradation via the ubiquitin-proteasome pathway. DDO3602 induces G2/M cell cycle arrest, DNA damage, inhibits cell migration, and exhibits antiproliferative activity in breast cancer cells. DDO3602 can be used in breast cancer-related research [1]. (Pink: PARP1 ligand; Blue: HSP90 ligand; Black: linker ).
In Vivo, DDO3602 (10-20 mg/kg; i.p.; every other day; 21 days) potently inhibits MCF-7 xenograft tumor growth in immunocompromised mice[1]. DDO3602 (20 mg/kg; i.v.; single dose) exhibits tumor-targeted pharmacokinetics in MCF-7 xenograft mice, with significantly higher accumulation in tumor tissue than normal tissues following a single 20 mg/kg intravenous dose[1].
In Vitro, DDO3602 (0-3 μM; 9 h) degrades PARP1 in human breast cancer MCF-7 cells in a dose-dependent manner, with a DC50 of 490.3 nM, and the degradation rate reaches 70.6% after incubation at 1 μM for 9 h[1]. DDO3602 (1 μM; 0-24 h) induces significant degradation of PARP1 in human breast cancer MCF-7 cells within 3 h, with nearly complete depletion achieved by 9 h[1]. DDO3602 (1 μM; 0-24 h) degrades the pre-existing PARP1 protein in MCF-7 human breast cancer cells, rather than inhibiting its synthesis[1]. DDO3602 (0-1 μM) exerts a stronger inhibitory effect on colony formation in human breast cancer MCF-7 cells than in normal mammary epithelial MCF-10A cells[1]. DDO3602 (0-10 μM; 72 h) inhibits the viability of MCF-7 human breast cancer cells with an IC50 of 0.189 μM; its potency is approximately 4-fold higher than that against MCF-10A normal mammary epithelial cells (IC50 = 0.744 μM) after 72 h of treatment[1]. DDO3602 (0.5-1 μM; 24 h) induces dose-dependent G2/M cell cycle arrest in human breast cancer MCF-7 cells[1]. DDO3602 (1 μM; 24 h) induces significant DNA double-strand break formation in MCF-7 human breast cancer cells (detected by γ-H2A.X accumulation)[1]. DDO3602 (0.1-1 μM; 48 h) significantly inhibits the migration of MCF-7 cells[1].
References:
[1]. Liu W, et al. HSP90 Mediates Targeted Degradation of Nonclient Protein PARP1 for Breast Cancer Treatment. Journal of medicinal chemistry. 2025 Oct 09;68(19):19933-19954.
In Vivo, DDO3602 (10-20 mg/kg; i.p.; every other day; 21 days) potently inhibits MCF-7 xenograft tumor growth in immunocompromised mice[1]. DDO3602 (20 mg/kg; i.v.; single dose) exhibits tumor-targeted pharmacokinetics in MCF-7 xenograft mice, with significantly higher accumulation in tumor tissue than normal tissues following a single 20 mg/kg intravenous dose[1].
In Vitro, DDO3602 (0-3 μM; 9 h) degrades PARP1 in human breast cancer MCF-7 cells in a dose-dependent manner, with a DC50 of 490.3 nM, and the degradation rate reaches 70.6% after incubation at 1 μM for 9 h[1]. DDO3602 (1 μM; 0-24 h) induces significant degradation of PARP1 in human breast cancer MCF-7 cells within 3 h, with nearly complete depletion achieved by 9 h[1]. DDO3602 (1 μM; 0-24 h) degrades the pre-existing PARP1 protein in MCF-7 human breast cancer cells, rather than inhibiting its synthesis[1]. DDO3602 (0-1 μM) exerts a stronger inhibitory effect on colony formation in human breast cancer MCF-7 cells than in normal mammary epithelial MCF-10A cells[1]. DDO3602 (0-10 μM; 72 h) inhibits the viability of MCF-7 human breast cancer cells with an IC50 of 0.189 μM; its potency is approximately 4-fold higher than that against MCF-10A normal mammary epithelial cells (IC50 = 0.744 μM) after 72 h of treatment[1]. DDO3602 (0.5-1 μM; 24 h) induces dose-dependent G2/M cell cycle arrest in human breast cancer MCF-7 cells[1]. DDO3602 (1 μM; 24 h) induces significant DNA double-strand break formation in MCF-7 human breast cancer cells (detected by γ-H2A.X accumulation)[1]. DDO3602 (0.1-1 μM; 48 h) significantly inhibits the migration of MCF-7 cells[1].
References:
[1]. Liu W, et al. HSP90 Mediates Targeted Degradation of Nonclient Protein PARP1 for Breast Cancer Treatment. Journal of medicinal chemistry. 2025 Oct 09;68(19):19933-19954.