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ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors.
- Source :
-
Cell reports. Medicine [Cell Rep Med] 2021 Jul 21; Vol. 2 (7), pp. 100350. Date of Electronic Publication: 2021 Jul 21 (Print Publication: 2021). - Publication Year :
- 2021
-
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 <superscript>V600E</superscript> 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.<br />Competing Interests: A.Y. has received honoraria and/or consultancy fees from Abbvie, Biopath, Curis, Epizyme, Janssen, Merck, Roche, Takeda, and Xynomic and has received research support from Janssen, Curis, Merck, BMS, Syndax, and Roche. S.T., S.G., and L.D. are employees and shareholders of Asana BioSciences. R.A.S. is a shareholder in and consultant to Asana BioSciences. S.T., R.A.S., and S.R. are inventors on three patents covering ASN007 and related compounds and their use in the treatment of cancer. The other authors declare no competing interests.<br /> (© 2021.)
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Cell Line, Tumor
Cell Proliferation drug effects
Extracellular Signal-Regulated MAP Kinases metabolism
Inhibitory Concentration 50
Mice, Nude
Neoplasms pathology
Phosphatidylinositol 3-Kinases metabolism
Protein Kinase Inhibitors chemistry
Pyrimidines pharmacology
Quinazolines pharmacology
Xenograft Model Antitumor Assays
Mice
Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors
Mutation genetics
Neoplasms enzymology
Neoplasms genetics
Protein Kinase Inhibitors pharmacology
raf Kinases genetics
ras Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2666-3791
- Volume :
- 2
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell reports. Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 34337566
- Full Text :
- https://doi.org/10.1016/j.xcrm.2021.100350