SCH772984

Biological Activity

SCH772984 is a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS. 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. SCH772984 induces tumor regressions in xenograft models at tolerated doses.

Protocol

Cell Experiment
Cell lines	BRAF- or RAS-mutant tumor cells
Preparation method	Cell proliferation experiments were carried out in a 96-well format (six replicates), and cells were plated at a density of 4,000 cells per well. At 24 hours after cell seeding, cells were treated with DMSO or a 9-point IC50 dilution (0.001–10 μmol/L) at a final concentration of 1% DMSO for all concentrations. Viability was assayed 5 days after dosing using the ViaLight luminescence kit (Lonza) following the manufacturer's recommendations (n = 6, mean ± SE). For the cell line panel viability assay, cells were treated with SCH772984 for 4 days and assayed by the CellTiterGlo luminescent cell viability assay (Promega).
Concentrations	0.001–10 μmol/L
Incubation time	4 days

Animal Experiment
Animal models	Female nude mice bearing human LOX BRAF-mutant/MiaPaCa KRAS-mutant pancreatic/ melanoma xenograft model
Formulation	normal saline
Dosages	12.5, 25, or 50 mg/kg for 14 days
Administration	intraperitoneally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

Customer Product Validations & Biological Datas

	Source	J Neurosci (2018). Figure 7. SCH772984 (Abmole Bioscience)
	Method	QRT-PCR
	Cell Lines	Primary cortical neurons
	Concentrations	5 nM, 50 nM
	Incubation Time	4 h
	Results	These results suggested that in addition to the increase in GluN2A protein levels in the synaptosomes and mitochondria, additional unknown mechanism(s), which could up-regulate the ERK-CREB signaling, might also contribute to the resistance of Hipk2-/- DA neurons to CCCP.
	Rating

	Source	Saudi Pharmaceutical Journal (2016) . Figure 2.SCH772984, produced by AbMole
	Method	MWT determination
	Cell Lines
	Concentrations	0, 0.1, 1, 10μg
	Incubation Time	3, 6, 9, 12, 15, 18 and 24 hr
	Results	Comparing model group with Sham group and intrathecal tube group, MWT shows no significant differences at different time (p>0.05); comparing model group with BCP group and intrathecal tube +BCP group, MWT shows significant differences at different time (p<0.05); comparing model group with BCP group, MWT shows significant differences (p<0.05); comparing BCP group and intrathecal tube +BCP group, MWT shows no significant differences (p>0.05).
	Rating

	Source	Saudi Pharmaceutical Journal (2016) . Figure 1.SCH772984, produced by AbMole
	Method	MWT determination
	Cell Lines
	Concentrations	0, 0.1, 1, 10μg
	Incubation Time	3, 6, 9, 12, 15, 18 and 24 hr
	Results	Comparing model group with Sham group and intrathecal tube group, MWT shows no significant differences at different time (p>0.05); comparing model group with BCP group and intrathecal tube +BCP group, MWT shows significant differences at different time (p<0.05); comparing model group with BCP group, MWT shows significant differences (p<0.05); comparing BCP group and intrathecal tube +BCP group, MWT shows no significant differences (p>0.05).
	Rating

Product Citations

• 

  J Neurosci 2018 Mar 26.

  HIPK2-mediated transcriptional control of NMDA receptor subunit expression regulates neuronal survival and cell death
  SCH772984 purchased from AbMole

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  Saudi Pharmaceutical Journal. 2016 May;24(3):354-62.

  Analgesic effect and possible mechanism of SCH772984 intrathecal injection on rats with bone cancer pain.
  SCH772984 purchased from AbMole

References

Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors.
Morris EJ, et al. Cancer Discov. 2013 Jul;3(7):742-50. PMID: 23614898.