Small molecules irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO: ≥ 40 mg/mL|
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions.
Ostrem JM, et al. Nature. 2013 Nov 28;503(7477):548-51. PMID: 24256730.
|Related Ras Products|
CID-1067700 (ML282) is a competitive inhibitors of nucleotide binding by Ras-related GTPases with a Ki of 13 nM for Rab7.
MLS000532223 is a selective inhibitor of Rho family GTPases, with EC50 ranging from 16 μM to 120 μM.
BI-3406 is a highly potent and selective SOS1::KRAS inhibitor (IC50=6 nM), which selectively binds to SOS1 and blocks the interaction with KRAS, irrespective of the KRAS mutation.
ZT-12-037-01 is a potent, selective, ATP-competitive STK19 inhibitor with IC50 values of 23.96 nM and 27.94 nM for STK19 (WT) and STK19 (D89N), respectively.
BI-2852 is a potent KRAS inhibitor that binds with nanomolar affinity to a pocket.
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