Unlocking the Potential of SC10914: A Potent and Selective PARP Inhibitor for BRCA1/2-Deficient Cancers

Poly(ADP-ribose) polymerase (PARP) inhibitors are drugs that interfere with DNA repair mechanisms, leading to an accumulation of double-strand breaks that are particularly problematic in cells with deficiencies in homologous recombination, such as those lacking BRCA function. The study introduces SC10914, a new potent PARP inhibitor with favorable pharmacokinetics, which has shown strong anti-proliferative effects against certain tumor cells, including those deficient in BRCA1, BRCA2, and PTEN.

In experiments, MDA-MB-436 and Vc8 tumor fragments were implanted into BALB/cA nude mice. The mice were divided into groups and treated with either a placebo, AZD2281, or varying doses of SC10914 for 21 days. SC10914 demonstrated significant in vivo anti-tumor efficacy at tolerable doses, with daily oral administration leading to tumor stasis in both types of xenografts. Notably, a lower dose of SC10914 was as effective as a higher dose of AZD2281.

Pharmacokinetic studies in rats revealed that SC10914 has a superior profile to AZD2281, with higher oral bioavailability, greater area under the curve (AUC), and longer half-life. The relationship between dosage and drug plasma exposure was also positive within a certain range. Additionally, SC10914 showed no inhibition of the hERG channel and no mutagenic effects in Ames tests using Salmonella typhimurium strains.

The findings suggest that SC10914 is a promising candidate for clinical development for the treatment of cancers with BRCA1/2 mutations, offering potent anti-tumor activity and improved pharmacokinetic properties compared to existing treatments.