WRN-IN-24

WRN-IN-24 is an orally active allosteric covalent inhibitor of the Werner syndrome RecQ DNA helicase (WRN), with an IC50 of 201 nM. It binds to a novel allosteric cavity, forming an additional hydrogen bond with K894, thereby functionally inhibiting WRN activity. WRN-IN-24 suppresses the proliferation of colorectal cancer cells and demonstrates dose-dependent antitumor activity in xenograft mouse models. This compound is applicable in research on cancers with high microsatellite instability, including colorectal cancer.

WRN-IN-24 (Compound 22) is a potent inhibitor of purified WRN helicase activity, with an IC 50 of 201 nM. It effectively suppresses the proliferation of HCT116 MSI-H colorectal cancer cells with an IC 50 of 49 nM and also inhibits the proliferation of SW48 MSI-H colorectal cancer cells, exhibiting an IC 50 of 48.0 nM. Additionally, in SW48 MSI-H cells, it activates the DNA damage response marker γH2AX with an EC 50 of 338 nM. WRN-IN-24 shows no antiproliferative activity in HT29 and MDA-MB-231 MSS cell lines, with IC 50 values both exceeding 10000 nM.

WRN-IN-24 (Compound 22), administered orally at doses of 5-20 mg/kg once daily for 21 days, has demonstrated the ability to inhibit tumor growth in the HCT116 (MSI-H) xenograft mouse model.