DS17701585 is a Highly Selective, Orally Active EP300 and CBP Inhibitor
Posted On 2022-06-23
DS17701585 (Compound 11) is a highly selective, orally active EP300 and CBP inhibitor with IC50 values of 0.15, 0.040, 0.45 and 0.70 µM against CBP, EP300, H3K27 and SOX2. Besides, DS17701585 has the potential for the research of cancer.
EP300 and its paralog CBP play an important role in post-translational modification as histone acetyltransferases (HATs). EP300/CBP inhibition has been gaining attention as an anticancer treatment target in recent years. Herein, DS17701585 is a potent and highly selective EP300/CBP inhibitor in a biochemical assay and cell-based assay. What’s more, DS17701585 shows selectivity for EP300, CBP, TIP60, MYST2, MYST4, PCAF, GCN5 with IC50 values of 0.15, 0.040, >50, >50, >50, >50, >50 µM, respectively. Moreover, DS17701585 shows suppression of SOX2 expression in LK2 cells with an IC50 value of 0.70 µM.
DS17701585 has improved metabolic stability in mouse liver microsomes.
DS17701585 shows moderate ADME profiles with 37% remaining mouse metabolic stability. Besides, this compound exhibits a 95.2% protein binding fraction in mouse plasma. what’s more, DS17701585 (50, 200 mg/kg; oral administration) demonstrates dose-dependent inhibition of SRY-box transcription factor 2 (SOX2) mRNA expression in a human lung squamous cell carcinoma cell line LK2-xenografted mouse model. Besides, we use Balb/c nude mice to establish the LK2 cell xenograft model. Additionally, the increasing suppression of SOX2 mRNA levels was correlated with increased plasma and tumor DS17701585 levels. Furthermore, the SOX2 mRNA suppression is 60% at 50 mg/kg and about 10% at 200 mg/kg.
In conclusion, DS17701585 is a potent, selectively, and orally active EP300 and CBP inhibitor with IC50 values of 0.15, 0.040, 0.45, and 0.70 µM against CBP, EP300, H3K27, and SOX2. Besides, DS17701585 inhibits SOX2 mRNA expression in a dose-dependent manner. Moreover, DS17701585 has the potential for the research of cancer.
Kanada R, et al. Bioorg Med Chem Lett. 2022 Jun 15;66:128726.