Discovery of Asn007, a Novel Inhibitor of Erk1/2, with a Preferential Activity in RAS- and RAF-Mutant Tumors

The RAS/RAF/MEK/ERK pathway is aberrantly activated in approximately 30% of human cancers. Selective inhibitors of MEK or BRAF have shown clinical activity in both solid tumors and hematologic malignancies, but responses are typically transient due to acquired resistance and feedback activation of ERK1/2. We developed a potent, selective ERK1/2 inhibitor, ASN007, with anti-tumor activity in both solid tumors and lymphoma models with BRAF and RAS mutations and also in a melanoma PDX model resistant to BRAF and MEK inhibitors. ASN007 synergizes with PI3K inhibitors both in vitro and in vivo. Our data show that the selective ERK1/2 inhibitor ASN007, alone or in combination with PI3K inhibitors, may offer a new therapeutic option for patients with RAS or MAPK pathway activated cancers.