YCH1899, an orally active PARP inhibitor, demonstrates potent inhibition of PARP1/2 with an IC50 of less than 0.001 nM. It shows marked antiproliferative efficacy against Olaparib-resistant (Capan-1/OP) and Talazoparib-resistant (Capan-1/TP) cells with IC50 values of 0.89 nM and 1.13 nM, respectively. Moreover, YCH1899 possesses favorable pharmacokinetic attributes in rats [1].

ARTD10/PARP10:10.8 nM, PARP15:51.623 nM, PARP2:<0.001 nM, PARP3:1.1 nM, PARP14:35.914 μM, PARP1:<0.001 nM, PARP7:7.3 nM, TNKS1:3.8 nM (EC50), TNKS2:12.4 nM, PARA6:9.5 nM, PARA11:2.166 μM, PARP12 (human):14.1 nM, PARP4:1.0 nM

YCH1899 exhibited significant antiproliferative activity against Capan-1, Capan-1/OP, and Capan-1/TP cells with corresponding IC50 values of 0.10, 0.89, and 1.13 nM [1]. At concentrations ranging from 0.001 to 1 nM for 4 hours, YCH1899 stabilized PARP1-DNA complexes and inhibited the formation of PARP [1]. Additionally, YCH1899 demonstrated inhibitory effects on the proliferation of both BRCA-mutated and wild-type cells (V−C8, V79, HCT-15, HCC1937) with IC50s between 1.19 and 44.24 nM after 3.5 hours of treatment [1]. When applied at 1 μM for 24 hours, YCH1899 induced DNA damage in Capan-1, Capan-1/OP, and Capan-1/TP cells, leading to a significant increase in γH2AX levels [1]. Finally, treatment with YCH1899 at 1 μM for 48 hours significantly reduced Homologous Recombination (HR) repair activity in U2OS-DR-GFP cells [1].

YCH1899, administered intravenously at a dose of 5 mg/kg, demonstrated moderate clearance in rats [1]. The compound successfully overcame Talazoparib resistance in xenograft mouse tumor models of MDA-MB-436/OP and Capan-1/R, with significant tumor volume reduction observed at oral doses of 6.25, 12.5, and 25 mg/kg once daily for 27 days and 12.5 and 25 mg/kg once daily for 21 days, respectively [1].