ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors

Cell Rep Med. 2021 Jul 21;2(7):100350. doi: 10.1016/j.xcrm.2021.100350. eCollection 2021 Jul 20.

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 BRAFV600E mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both in vitro and in vivo 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.

Keywords: ASN007; ERK; KRAS; PI3K; RAF/RAS-driven cancers; biomarker; combinational therapy; kinase inhibitor; lymphoma; solid tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Inhibitory Concentration 50
  • Mice
  • Mice, Nude
  • Mutation / genetics*
  • Neoplasms / enzymology*
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology
  • Quinazolines / pharmacology
  • Xenograft Model Antitumor Assays
  • raf Kinases / genetics*
  • ras Proteins / genetics*

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinazolines
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • ras Proteins
  • copanlisib