D-I03 is a selective inhibitor of RAD52 with a corresponding Kd value of 25.8 μM. D-I03 inhibits ssDNA annealing via RAD52 and D-loop formation with IC50 values of 5 μM and 8 μM, respectively.
in vitro
D-I03 (0-10 μM; on days 1 and 3; Capan-1 and UWB1.289 cells) treatment preferentially suppressed the growth of Capan-1 and UWB1.289 cells in a concentration-dependent manner . D-I03 inhibits RAD52 foci formation induced by cisplatin in BCR-ABL1-positive BRCA1-deficient 32Dcl3 murine hematopoietic cell line that expresses GFP-RAD52. In the presence of D-I03 (2.5 μM), the fraction of cells with RAD52 foci is decreased, from 38.7% to 171%; at the same time, the fraction of Cisplatin-treated cells without foci is increased from 48.4% to 71.9%. D-I03 does not effect on RAD51 foci induced by Cisplatin. Also, D-I03 alone induce neither RAD51 foci nor RAD52 foci (in BRCA1-deficient cells) indicating low genotoxicity of D-I03.
Cell Proliferation Assay
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Cell Line:
Capan-1 (BRCA2 ? ) and UWB1 .289 (BRCA1 + ) cells
Concentration:
0 μM, 2.5 μM, 5 μM, or 10 μM
Incubation Time:
On days 1 and 3
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Result:
Preferentially suppressed the growth of Capan-1 and UWB1.289 cells.
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in vivo
D-I03 (50 mg/kg/day; intraperitoneal injection; daily; for 7 days; nu/nu mice) treatment reduces BRCA1-deficient MDA-MB-436 tumor growth . Talazoparib puls D-I03 does not affect the growth of BRCA1-proficient tumors and does not exert any significant toxicity against normal tissues and organs. Pharmacokinetic and toxicity studies indicate that maximal tolerated dose of D-I03 is ≥50 mg /kg, and t 1/2 is 23.4 hours, resulting in >1 μM maximal concentration in peripheral blood.
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Animal Model:
Nu/nu mice injected with BRCA1-deficient MDA-MB-436 cells
