Src kinase family is a family of non-receptor tyrosine kinases. DGY-06-116 is a selective Src inhibitor. DGY-06-116 is an SRC-directed covalent kinase inhibitor that displays efficient covalent target labeling and irreversible cellular inhibition of SRC signaling. Furthermore, DGY-06-116 inhibits SRC for an extended duration, likely due to its ability to covalently bind the target.

DGY-06-116 induces strong growth inhibitory effects across all three cell lines with GR50 values of 0.3, 0.5, and 0.3 μM, respectively. Moreover, DGY-06-116 exhibits potent antiproliferative effects in non-small cell lung cancer cell lines harboring SRC activation. Thus, DGY-06-116 selectively modifies SRC Cys277. DGY-06-116 shows comparable IC50, 1 h values for mutant and wild-type Src, suggesting that reversible binding substantially contributes to the potency of this compound.

Covalent and selective SRC targeting in these cell lines can achieve potent inhibition of growth and proliferation. DGY-06-116 inhibits p-SRCY416 signaling in both H1975 and HCC827 cells. Furthermore, DGY-06-116 also leads to cytotoxic effects in HCC827 and MDA-MB-231 cells. DGY-06-116 leads to inhibition of p-SRCY416 at 2 and 4 h postdosing, compared to the vehicle controls. DGY-06-116 is capable of inducing potent SRC binding and inhibition of SRC signaling in cells.

In vivo, researchers administrated DGY-06-116 (5 mg/kg i.p. in 5% DMSO/95% D5W) in B6 mice. DGY-06-116 exhibits a short half-life and high exposure (T1/2=1.29 h, AUC=12746.25 min·ng/mL).

Together, these results indicate that covalent inhibition of SRC by DGY-06-116 leads to potent and sustained target engagement, compared to reversible SRC compounds. Overall, DGY-06-116 exhibits sustained inhibition of Src signaling both in vitro and in vivo.

Guangyan Du, et al. Structure-Based Design of a Potent and Selective Covalent Inhibitor for SRC Kinase That Targets a P-Loop Cysteine. J Med Chem. 2020 Feb 27;63(4):1624-1641.