D-I03 is a selective RAD52 inhibitor with a Kd of 25.8 µM. It specifically inhibits RAD52-dependent single-chain annealing (SSA) and D-loop formation, with IC50 values of 5 µM and 8 µM, respectively. D-I03 also inhibits the growth of BRCA1 and BRCA2 deficient cells and prevents the formation of damage-induced RAD52 foci, but does not affect RAD51 foci induced by Cisplatin.

D-loop:8 µM, single-chain annealing (SSA):5 µM, RAD52:25.8 µM (Ki)

D-IO3 (0-10 μM; on Days 1 and 3; Capan-1 and UWB1.289 cells) treatment preferentially inhibited the growth of Capan-1 and UWB1.289 cells in a concentration-dependent manner . D-IO3 inhibited cisplatin-induced RAD52 foci formation in the BCR-ABL1-positive BRCA1-deficient 32Dcl3 mouse hematopoietic cell line expressing GFP-RAD52. In the presence of D-IO3 (2.5 μM), the proportion of cells with RAD52 lesions decreased from 38.7% to 171%; meanwhile, the proportion of cisplatin-treated cells without lesions increased from 48.4% to 71.9%. D-IO3 had no effect on cisplatin-induced RAD51 foci. Similarly, D-I03 alone (in BRCA1-deficient cells) induced neither RAD51 nor RAD52 lesions, indicating that D-I03 has low genotoxicity[1].

D-IO3 (50 mg / kg / day; intraperitoneal injection; daily; 7 consecutive days; nu / nu mice) treatment can reduce the growth of BRCA1-deficient MDA-MB-436 tumors. Talazoparib puls D-I03 does not cause any obvious toxicity to normal tissues and organs, and does not affect the growth of BRCA1-positive tumors. Pharmacokinetic and toxicity studies have shown that the maximum tolerated dose of D-I03 is ≥50mg / kg and t1 / 2 is 23.4 hours, resulting in a maximum concentration in peripheral blood> 1μM[1].