MEK inhibitor (BI 3011441)

Role of the RAS/RAF/MEK/ERK signaling pathway

MEK is a component of the mitogen-activated protein kinase (MAPK) pathway, a signaling cascade also involving RAS and ERK that regulates gene expression, drives proliferation, and prevents apoptosis.² Following sequential phosphorylation and activation of RAF and MEK, activated ERK phosphorylates more than 200 substrates, including transcription factors that regulate genes involved in mitogenic signaling.³

Mechanism of action

BI 3011441 (LNP3794) is a small-molecule allosteric inhibitor that binds adjacent to the ATP pocket of MEK, resulting in inhibition of MEK kinase activity. The rationale for targeting MEK is to prevent downstream ERK signaling. In tumor cells, treatment with BI 3011441 results in downregulated MAPK pathway signaling, reduced cell proliferation, and induction of apoptosis.¹

Combination therapy

MEK functions downstream of SOS1, KRAS, and RAF. MAPK pathway activity is strictly regulated by the gatekeeper ERK, which also mediates negative-feedback loops within the MAPK pathway – for example, by phosphorylation of upstream components such as receptor tyrosine kinases, SOS1, and RAF.⁴ Drugs that selectively inhibit MEK are able to block MAPK pathway activity, leading to reduced cell proliferation and cell death.

However, negative feedback resulting from MEK inhibition can lead to an increase in SOS1-mediated KRAS activation, which subsequently results in re-activation of the MAPK pathway.⁴ SOS1::KRAS inhibition* reduces the formation of GTP-loaded, activated KRAS, and thereby inhibits MAPK pathway signaling.⁵ By simultaneously blocking the ERK-mediated negative-feedback loop, SOS1::KRAS inhibition sensitizes KRAS-dependent cancers to MEK inhibition, resulting in complete blockade of the pathway and tumor regression in vivo.⁵

Further clinical studies of BI 3011441 in combination with a SOS1::KRAS inhibitor (BI 1701963) are expected to commence in 2021.¹