Monday, May 18, 2015

Drugs in Clinical Pipeline: SCH772984

SCH772984 [(R)-1-(2-oxo-2-(4-(4-(pyrimidin-2-yl)phenyl)piperazin-1-yl)ethyl)-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)pyrrolidine-3-carboxamide] is a novel and selective inhibitor of ERK1/2 that displays activity of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.

SCH772984 was identified using an affinity-based mass spectroscopy high-throughput platform. A library of approximately 5 million compounds was screened for binding to the unphosphorylated form of the ERK2 protein. Synthetic chemistry efforts improved enzymatic potency and selectivity, culminating in the synthesis of the ATP-competitive compound SCH772984. SCH772984 potently inhibited ERK1 and ERK2 activity with IC50 values of 4 and 1 nM, respectively. Notably, SCH772984 did not inhibit the kinase MEK1 even at concentration greater than 10 uM. SCH772984 is highly selective, with only seven kinases of 300 tested showing more than 50% inhibition at a concentration of 1 ┬ÁM [CLK2, FLT4, GSG2, MAP4K4, MAPK1, MINK1, PRKD1, TTK (50-100% inhibition)] [1].

The activity of SCH772984 is as follows:

IC50 (ERK1 enzyme assay) = 4 nM
IC50 (ERK2 enzyme assay) = 1 nM

Common Name: SCH772984
Synonyms:  SCH772984; SCH-772984; SCH 772984
IUPAC Name: (R)-1-(2-oxo-2-(4-(4-(pyrimidin-2-yl)phenyl)piperazin-1-yl)ethyl)-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)pyrrolidine-3-carboxamide
CAS Number: 942183-80-4
Mechanism of Action: Kinase Inhibitor; ERK 1/2 Inhibitor
Indication: Various Cancers; Anti-tumor Therapy
Development Stage: Investigational
Company: Merck

1. Morris,  E. J.; et. al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov 2013, 3(7), 742-750.