RET-IN-3 is a selective RET V804M kinase inhibitor

**Background**

The Rearranged during Transfection (RET) proto-oncogene encodes a receptor tyrosine kinase that plays a critical role in various developmental processes. Mutations in the RET kinase domain are frequently associated with hereditary multiple endocrine neoplasia (MEN) and sporadic cancers, particularly medullary thyroid carcinoma. Among these, the V804M mutation is a common “gatekeeper” mutation that often confers resistance to first-generation RET inhibitors by altering the ATP-binding pocket. Developing highly selective inhibitors that can target the V804M mutant while sparing wild-type RET and other kinases is essential for improving therapeutic outcomes in RET-driven cancer. In this context, we will introduce a selective RET V804M kinase inhibitor – RET-IN-3.

**Definition**

RET-IN-3 is a selective RET V804M kinase inhibitor with an IC50 value of 19 nM. According to the RET-IN-3 description, this compound is specifically designed to target the mutant form of the kinase to overcome resistance mechanisms.

**In Vitro Studies**

The RET-IN-3 biological activity has been extensively evaluated to determine its selectivity and potency. In vitro assays demonstrate that RET-IN-3 exhibits significant selectivity, being 16-fold more selective for the V804M mutant compared to wild-type RET (wt-RET) and 410-fold more selective compared to KDR. Furthermore, the RET-IN-3 in vitro cellular effects were assessed using human BaF3 cells. In these studies, RET-IN-3 inhibited the viability of BaF3 cells expressing the RET V804M mutant with an IC50 of 0.11 μM after 48 hours of incubation, as measured by celltiter glo luminescence assay. In contrast, the IC50 for the inhibition of BaF3 cells expressing wild-type RET was 4 μM, and for those expressing KDR, it was 9 μM. These results highlight the compound’s ability to selectively target the mutant kinase over its wild-type counterpart and other related kinases. In conclusion, RET-IN-3 is a potent and selective inhibitor of the RET V804M mutant kinase, providing a valuable tool for cancer research.

Keywords

RET-IN-3, 2414374-53-9, RET, Inhibitor, inhibitor, inhibit

References

[1] Rebecca Newton, et al. Discovery and Optimization of wt-RET/KDR-Selective Inhibitors of RET V804M Kinase. ACS Med Chem Lett. 2020 Feb 28;11(4):497-505.