D-I03

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.

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 indicates 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.