AMG-510

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.

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.

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).