IK-595

IK-595 is a highly potent MEK1/MEK2 inhibitor with a high affinity of 7.39 nM. It blocks EGF-induced ERK1/2 phosphorylation in AsPC-1 cells, with an IC50 value of 0.1 nM. This compound is orally active and capable of crossing the blood-brain barrier, and it can be applied in studies related to cancers with abnormal Ras/MAPK pathways.

IK-595 significantly enhances the interaction between MEK and CRAF in HCT-116 cells and promotes the interaction between MEK and BRAFV600E, class II, and class III mutants in HT-29, NCI-H1755, and NCI-H1666 cells at a concentration of 3 nM for 4 hours. When combined with sotorasib (62.5 nM), IK-595 (25 nM; long-term monitoring) inhibits cell viability in NCI-H358 cells for over 30 days. IK-595 (3 nM; 120 hours) in combination with sotorasib (1000 nM) induces a higher level of apoptosis in NCI-H358 cells than other MEK inhibitor combinations. Additionally, IK-595 (10 nM; 120 hours) paired with RMC-7977 (1 nM) enhances apoptosis in NCI-H358 cells. For cells resistant to sotorasib (NCI-H358-R), IK-595 (3 nM; long-term monitoring) with sotorasib (250 nM) blocks cell growth and inhibits ERK1/2 phosphorylation.

In a xenograft mouse model, IK-595 (6 mg/kg; oral administration; every other day) demonstrates antitumor activity. Additionally, IK-595 (6 mg/kg; oral administration; single dose) exhibits superior brain pharmacodynamic activity in mice with intracranial and subcutaneous A549 tumor implants.