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Pfizer Oncology
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The safety and efficacy of this agent(s), or use in this setting, has not been established or is subject to confirmation. For an agent(s) whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.

MEK Brain Penetrant Inhibitor

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MEK Brain Penetrant Inhibitor

PF-07799544/ARRY-134 is an investigational compound. Its safety and efficacy have not been established.

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Overview + Rationale

  • The mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 are upstream regulators of the extracellular signal-related kinase (ERK) pathway 
  • 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 types 
  • Current MEK inhibitors appear to be only modestly brain penetrant 
  • Acquired MEK mutations account for resistance to approved BRAF/MEK inhibitor combinations (prevalence 7-10%) 
  • Despite survival improvements in BRAF metastatic tumors with ICI & targeted therapy, brain metastases remain a major cause of morbidity and mortality 

  • Drug delivery across the blood brain barrier (BBB) is a factor that requires attention to address this unmet need

     

RATIONALE FOR CANCER TYPE
  • PF-07799544 is a brain-penetrant, by BRAF mutations and MAPK signaling 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

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 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 selective inhibitor PF-07799933, has demonstrated anti-tumor activity in non-clinical models of intracranial disease that are driven 
  • PF-07799544 is a brain-penetrant, by BRAF mutations and MAPK signaling

Inhibition

Stage of Development

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Advanced Solid Tumors
Phase 1 Monotherapy and Combination
This information is current as of October 30th 2024.

BRAF, a serine/threonine protein kinase; ICI, immune checkpoint inhibitors; KRAS/NRAF, a family of genes that encode proteins that have a pivotal cytoplasmic role in cell signaling; MAPK, mitogen-activated protein kinase

REFERENCES:  Pfizer, Data on file. July 2022; National Cancer Institute. NCI Drug Dictionary: binimetinib. Accessed February 22, 2020; Tawbi HA et al, Lancet Oncol. 2021 Dec;22(12):1692-1704; Vaidhyanathan S et al, Drug Metab Dispos. 2014 Aug: 42(8):1292-1300; Johnson D, et al. Eur J Cancer 2015 Dec; 51 (18): 2792-9; ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05538130.  Accessed October 21, 2024.