RMC-4550

RMC-4550 inhibits purified, activated full length human SHP2 with an IC50 of 1.55 nM, and has cellular IC50 of 39 nM in PC9 cells with a pERK readout. RMC-4550 has no detectable inhibitory activity up to 10 µM against the catalytic domain of SHP2, a panel of 14 additional protein phosphatases, and a panel of 468 protein kinases. RMC-4550 exhibits low to moderate cross species in vitro intrinsic clearance (3.6-24 µL/min/million cells) in hepatocytes, a high passive permeability (458 nm/s) and efflux ratio of 1^[1].

30,000 HEK-293 cells per well are plated in 96-well plates in Biotin-free RPMI supplemented with 0.1% fetal bovine serum, 0.02% bovine serum albumin and 1% penicillin/streptomycin. Expression of SOS1 constructs is induced by the addition 0.1 μg/mL doxycycline for 24 hours. Cells are treated with serial 3-fold dilutions of RMC-4550 diluted in biotin-free media supplemented with 0.02% bovine serum albumin and 1% penicillin/streptomycin (final DMSO concentration equivalent to 0.1%) for one hour. For the final 5 minutes of drug treatment, cells are stimulated with 50 ng/mL EGF, lysed and subjected to ERK1/2 phosphorylation analysis.

RMC-4550 has moderate to high bioavailability and has a half-life amenable for once daily oral administration. In the EGFR-driven KYSE-520 human esophageal cancer xenograft model, RMC-4550 has a dose dependent efficacy consistent with target modulation, assessed by phospho-ERK inhibition in tumors. RMC-4550 is well tolerated at doses that achieved maximal and sustained efficacy in this model^[1].