General
Preferred name
sotorasib
Synonyms
AMG-510 ()
AMG-510 racemate ()
(R)-38 ()
AMG-510 ()
Sotorasib (racemate) ()
Sotorasib isomer ()
AMG-510 (racemate) ()
AMG-510 isomer ()
Sotorasib (AMG510) racemate ()
(S)-AMG-510 ()
CT-AMG510AMG-510AMG510 ()
Kras mutant-targeting amg 510 ()
Lumykras ()
Lumakras ()
Kras g12c inhibitor 9 ()
AMG510 ()
P&D ID
PD121846
CAS
2252403-56-6
2296729-00-3
Tags
available
probe
covalent binder
drug
Drug indication
Non-small-cell lung cancer
Neoplasm
Drug Status
approved
investigational
Max Phase
4.0
First approval
2021
Probe info
Probe type
experimental probe
Probe sources
Probe targets
[[ compound.targets[t].gene_name ]]
Probe control
Probe control not defined
Orthogonal probes
9
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
MOA
Covalent Inhibitor;Mutant G12C specific
COMMENT
AMG-510 is the potent R-atropisomer [t1/2 (Racemization) >180 years at 25 °C, ΔG⧧rotation > 31 kcal/mol]. The non-specific reactivity of AMG 510 with GSH is relatively slow (t1/2 = 196 min/within the range of clinical acrylamides). “Rat and dog pharmacokinetic parameters for (R)-38/AMG 510 are in line with those observed in mouse, with reasonable oral bioavailability observed in all species, relatively short half- in all species […] but durable covalent inhibition of KRASG12C could be achieved without continuous drug exposure” (extract from 10.1021/acs.jmedchem.9b01180). AMG-510 was approved to start Phase 2 clinical trials in December 2019. Jul 30 2020 - 1:41pm; AMG 510 (compound 38) is a potent and selective covalent inhibitor of KRASG12C. It was derived by SAR and pharmacological optimisation of a series of compounds built upon the principle of covalently targeting the reactive cysteine residue of KRASG12C. As such it is selective for KRASG12C over other RAS mutants. Utilising A549 (KRASG12S mutant) cells as a control comparator. AMG 510 was >7000x more potent at reducing the viability of KRASG12C PaCa-21 cells (IC50 36.5 vs 0.005 uM respectively). The IC50 for suppression of pERK in PaCa-21 cells is 68nM. In addition to detailed SAR and crystallography demonstrating an interaction with a cryptic pocket (H95, Y96, Q99) of KRASG12C, mass spectrometry excluded promiscuous cysteine reactivity. AMG 510 is orally available and shows in vivo efficacy that correlates with pERK suppression at the 30-100mg/kg dose range in nude mice bearing PaCa-2. Preliminary data from phase 1 human evaluation has demonstrated tolerability and antitumor activity when administered as monotherapy to patients with advanced KRASG12C solid organ malignancy. Jul 30 2020 - 1:52pm; AMG-510 is a covalent inhibitor of KRASG12C, specifically targeting the mutant cysteine-12 residue. It is created by leveraging the ARS-1620 structure and the exploitation of the cryptic pocket with H95, Y96, and Q99 in KRASG12C. It is a highly potent, selective and orally bioavailable chemical probe suitable for studies with in vitro and in vivo model systems. Activity: AMG 510 inhibits pERK signalling in cells with IC50 of 68 nM, which is supported by the PD data showing its time-dependent inhibition of pERK in mouse models. It also showed potent in vivo activity with TGI of 86% at 10 mg/kg and significant tumor regression at 30 mg/kg in a MIA PaCa-2 mouse model. Target engagement: Target engagement was supported by the cocrystalization structure of AMG 510 in complex with GDP-KRASG12C where the quinazolinone core of AMG 510 occupies the KRAS switch II pocket and the acrylamide moiety making a covalent bond with C12. Ligand occupancy in vivo was demonstrated by efficient covalent modification of KRASG12C by AMG 510 to near completion within two hours. Selectivity: It is a highly selective compound for covalent modification of KRASG12C. In a cysteine proteome profiling studies, only the KRASG12C C12 peptide was covalently modified by AMG 510, of 6451 cysteine-containing peptides profiled. Cell viability assays showed selective killing of cancer cells with KRASG12C (MIA PaCa-2) over those with other KRAS mutations (KRAS p.G12S A549 cells). Aug 13 2020 - 9:18am
DESCRIPTION
Sotorasib (AMG510) is a covalent KRASG12C inhibitor that was developed by Amgen for anti-tumour potential in KRASG12C-driven cancers. It was the first KRAS-targeting drug to be approved for clinical use.
(GtoPdb)
DESCRIPTION
Sotorasib (AMG-510) is a first-in-class, orally bioavailable, and selective KRAS G12C covalent inhibitor. Sotorasib irreversibly inhibits KRAS G12C by locking it in an inactive GDP-bound state. Sotorasib leads to the regression of KRAS G12C?mutated locally advanced or metastatic non?small cell lung cancer (NSCLC)[1][2][3][4][5][6].
PRICE
83
PRICE
136
MOA
Covalent Inhibitor
(Chemical Probes.org)
DESCRIPTION
(S)-AMG-510 is the S-type compound of AMG-510 (Sotorasib), which effectively and selectively inhibits KRASG12C through covalent interaction with mutant cysteine, thereby promoting clinical efficacy in KRASG12C tumors.
(TargetMol Bioactive Compound Library)
DESCRIPTION
Sotorasib (AMG-510) is an orally active and selective covalent inhibitor of KRAS G12C. Sotorasib binds to the GDP state of the inactive conformation of KRAS G12C and inhibits KRAS and its downstream signaling. Sotorasib exhibits inhibitory activity against KRAS G12C mutant tumors.
(TargetMol Bioactive Compound Library)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
8
Organisms
0
Compound Sets
17
ChEMBL Approved Drugs
ChEMBL Drugs
Chemical Probes.org
CovalentInDB
CovBinderInPDB
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugMAP
Guide to Pharmacology
High-quality chemical probes
MedChem Express Bioactive Compound Library
NIH Approved Oncology Drugs
ReFrame library
Selleckchem Bioactive Compound Library
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
22
Molecular Weight
560.23
Hydrogen Bond Acceptors
8
Hydrogen Bond Donors
1
Rotatable Bonds
5
Ring Count
5
Aromatic Ring Count
4
cLogP
4.48
TPSA
104.45
Fraction CSP3
0.3
Chiral centers
1.0
Largest ring
6.0
QED
0.36
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target
Ras
p38 MAPK
KRAS G12C
Kras
MOA
K-Ras inhibitor
Orthogonal probe
ARS-1620
Pathway
GPCR/G protein
MAPK/ERK Pathway
MAPK
Target class
Enzyme
Target subclass
GTPase
Control
Compound-8
Source data
