Targeting ERK1/2 with AZD0364: A Promising Therapeutic Approach for NSCLC

The RAS/MAPK pathway is a crucial factor in the development of cancer, being disrupted in around 30% of human malignancies, often due to BRAF or RAS gene mutations. The pathway's central enzymes, ERK1 and ERK2, are potential therapeutic targets, especially since resistance to BRAF and MEK inhibitors can involve the reactivation of this pathway. The abstract introduces AZD0364, a novel ERK1/2 inhibitor identified through a scaffold hopping strategy that leverages conformational modeling and structure-based design, along with unique chemistry involving the opening of a sulfamidate ring.

AZD0364 has demonstrated high potency in cellular assays targeting a key substrate on the MAPK pathway, with an IC50 of 6 nM for inhibiting phospho-p90RSK1 in BRAFV600E mutant A375 cells. It is a selective kinase inhibitor, affecting only 10 out of 329 tested kinases at concentrations exceeding 50% at 1 μM. The compound also exhibits a long residence time on the ERK2 protein, as determined by surface plasmon resonance (SPR), with a pKd of 10 and a dissociation half-life (t1/2) of 277 minutes.

AZD0364's in vitro potency and selectivity are matched by favorable physico-chemical properties, including an estimated maximum absorbable dose exceeding 4 grams, and good oral bioavailability across different species, suggesting a low predicted human dose. In vivo studies using xenograft models have shown that AZD0364 can inhibit phospho-p90RSK1 in tumors in a dose-dependent manner and induce tumor regression in KRAS mutant NSCLC Calu 6 xenograft models. Additionally, AZD0364 has been shown to be safely and effectively combined with the MEK1/2 inhibitor selumetinib in KRAS mutant NSCLC xenograft models.

The research was presented by Iain Simpson, Mark J. Anderton, and colleagues at the American Association for Cancer Research Annual Meeting in 2018.