ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34337566.
- Also identified by DOI 10.1016/j.xcrm.2021.100350 and PMC identifier 8324497.
- Licence recorded as CC BY-NC-ND.
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Abstract
Inhibition of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) offers a promising therapeutic strategy in cancers harboring activated RAS/RAF/MEK/ERK signaling pathways. Here, we describe an orally bioavailable and selective ERK1/2 inhibitor, ASN007, currently in clinical development for the treatment of cancer. In preclinical studies, ASN007 shows strong antiproliferative activity in tumors harboring mutations in BRAF and RAS (KRAS, NRAS, and HRAS). ASN007 demonstrates activity in a BRAF<sup>V600E</sup> mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both <i>in vitro</i> and <i>in vivo</i> due to dual inhibition of RAS/MAPK and PI3K survival pathways. Our data provide a rationale for evaluating ASN007 in RAS/RAF-driven tumors as well as a mechanistic basis for combining ASN007 with PI3K inhibitors.
Medical subject headings
- Extracellular Signal-Regulated MAP Kinases
- Mutation
- Neoplasms
- Protein Kinase Inhibitors
- raf Kinases
- ras Proteins