BackMEK Brain Penetrant Inhibitor
PF-07799544 is an investigational compound. Its safety and efficacy have not been established.
Overview + Rationale
RATIONALE FOR CANCER TARGET
- The mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 are upstream regulators of the extracellular signal-related kinase (ERK) pathway1
- MEK1/2 are dual-specificity threonine/tyrosine kinases that play roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types2
- Current MEK inhibitors appear to be only modestly brain penetrant3
- Acquired MEK mutations account for resistance to approved BRAF/MEK inhibitor combinations (prevalence 7-10%)4
- Despite survival improvements in BRAF metastatic tumors with ICI & targeted therapy, brain metastases remain a major cause of morbidity and mortality3
- Drug delivery across the blood brain barrier (BBB) is a factor that requires attention to address this unmet need5
OVERVIEW
- PF-07799544 drives anti-tumor activity in BRAF-mutant xenograft models when in combination with BRAF inhibitors and shows drug exposure in the brain and activity in intracranial tumor models
- PF-07799544, in combination with the brain penetrant BRAF dimer selective inhibitor PF-07799933, has demonstrated anti-tumor activity in non-clinical models of intracranial disease that are driven by BRAF mutations and MAPK signaling
Mechanism of Action
- In pre-clinical models, PF-07799544 selectively binds and affects the MEK1/2 kinases, slowing both signal transduction and proliferation across MAPK pathway-driven cell lines
- PF-07799544 is a brain-penetrant, reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activity
- In vitro, PF-07799544 showed activity related to both ERK phosphorylation and cellular proliferation across select cell lines harboring activating mutations in BRAF, KRAS, or NRAS
Inhibition
Stage of Development
Advanced Solid Tumors
Phase 1 Monotherapy and Combination