https://astx.com/wp-content/uploads/2019/11/logo_white.png 0 0 webadmin https://astx.com/wp-content/uploads/2019/11/logo_white.png webadmin2020-07-01 15:32:092020-07-01 15:32:092017 EORTC: Characterisation of a novel ERK1/2 inhibitor, which modulates the phosphorylation and catalytic activity of ERK1/2
2017 EORTC: Characterisation of a novel ERK1/2 inhibitor, which modulates the phosphorylation and catalytic activity of ERK1/2
Characterisation of a novel ERK1/2 inhibitor, which modulates the phosphorylation and catalytic activity of ERK1/2
- The MAPK pathway is commonly hyper-activated in human cancers due to the occurrence of oncogenic mutations in RAF and RAS, and multiple studies have demonstrated that MAPK pathway inhibition suppresses the growth of such cancer cells.
- MAPK inhibition has been clinically validated by BRAF and MEK inhibitors, which are approved for the treatment of BRAFV600E-mutant melanoma and NSCLC. However, response to such agents is often short-lived due to the onset of resistance mechanisms that result in re-activation of ERK1/2 (ERK) signalling1,2.
- RAF and MEK inhibitors have also been clinically tested in other cancers, including BRAF-mutant colorectal (CRC) and KRAS-mutantNon-small cell lung cancer (NSCLC), where they had limited clinical activity3,4.
- As ERK is the primary downstream effector of the MAPK pathway, it is hypothesized that ERK inhibitors may prove to be less susceptible to oncogenic bypass than RAF and MEK inhibitors and therefore have the potential to overcome the limitations of RAF and MEK inhibitors.
- Using fragment-based drug discovery we have developed a novel, potent and selective ERK inhibitor, which inhibits in vitro ERK catalytic activity with a low nMIC50 value and has strong anti-proliferative effects in a wide range of MAPK-activated cell lines.
- In addition to inhibiting ERK catalytic activity, the compound also inhibits the phosphorylation of ERK by MEK and confers a decrease in cellular pERKlevels in both BRAF-mutant and KRAS-mutant cell lines (in vitro and in in vivo pharmacodynamic[PD] studies).
- Once daily oral dosing of the lead compound (50 mg/kg) conferred significant anti-tumoractivity in a range of in vivo models.
- These data support the further optimisation of this series of compounds for clinical development.