Abstract B150: ASN007, a novel oral ERK inhibitor, shows robust antitumor activity in RAS mutant cancer models

Abstract

Abstract The extracellular-signal-regulated kinases, ERK1 and ERK2 (ERK1/2), are key players in the RAS/RAF/MEK signaling pathway. This pathway is frequently hyper-activated in a wide range of cancers through mutations in upstream targets such as BRAF, RAS, and receptor tyrosine kinases. Inhibition of ERK1/2 offers a promising therapeutic strategy for these cancers, particularly the ones driven by RAS mutations. In order to inhibit this critical node of the RAS/RAF/MEK pathway, we discovered and characterized ASN007, a novel compound that shows potent inhibition of ERK1/2 kinases in a biochemical assay with low single-digit nM IC50 values. ASN007 showed a slow dissociation rate (long target residence time) as compared to several other known ERK inhibitors. In mechanistic cell-based assays, ASN007 inhibited the phosphorylation of ERK1/2 substrates such as RSK1, FRA1, and Elk1 in various cell lines. ASN007 showed single-digit nanomolar antiproliferative activity that was selective for MAPK-pathway dependent cancer cell lines. Indeed, ASN007 showed much more potent activity against a broader panel of KRAS, NRAS, and HRAS mutant cell lines compared to other ERK1/2 inhibitors such as BVD-523 and GDC-0994. In a daily oral dosing regimen, ASN007 demonstrated strong inhibition of tumor growth in multiple BRAF and KRAS mutant xenograft models in mice and was well tolerated at efficacious doses. Of note, ASN007 also showed strong efficacy using various intermittent dosing regimens. ASN007 has a good pharmacokinetic profile in preclinical species and does not exhibit significant inhibition of CYP enzymes or hERG channel. IND-enabling studies are ongoing in preparation for a phase 1 clinical trial to evaluate oral ASN007 in patients with BRAF and K- , H- , and N-RAS mutant cancers Citation Format: Sanjeeva P. Reddy, Dhanalakshmi Sivanandhan, Purushottam Dewang, Niranjan Rao, Roger A. Smith, Scott K. Thompson. ASN007, a novel oral ERK inhibitor, shows robust antitumor activity in RAS mutant cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B150.