Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)

The RAS/MAPK pathway is a major driver of oncogenesis
and is dysregulated
in approximately 30% of human cancers, primarily by mutations in the
BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1
and ERK2) serve as central nodes within this pathway. The feasibility
of targeting the RAS/MAPK pathway has been demonstrated by the clinical
responses observed through the use of BRAF and MEK inhibitors in BRAF
V600E/K metastatic melanoma; however, resistance frequently develops.
Importantly, ERK1/2 inhibition may have clinical utility in overcoming
acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway
reactivation has occurred, such as relapsed BRAF V600E/K melanoma.
We describe our structure-based design approach leading to the discovery
of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364
exhibits high cellular potency (IC50 = 6 nM) as well as
excellent physicochemical and absorption, distribution, metabolism,
and excretion (ADME) properties and has demonstrated encouraging antitumor
activity in preclinical models.