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An Internally Controlled Quantitative Target Occupancy Assay for Covalent Inhibitors.

ABSTRACT: Assessing target occupancy is critical for establishing proof-of-mechanism for novel inhibitors and to determine whether robust target inhibition can be achieved at tolerated doses. This is challenging in the clinic using conventional methods due to the need for untreated controls. We describe a new mass spectrometry approach to quantitatively assess target occupancy for covalent inhibitors that does not require untreated controls, and apply the method to the KRAS^G12C inhibitor ARS-1620.

SUBMITTER: Hansen R

PROVIDER: S-EPMC6156402 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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An Internally Controlled Quantitative Target Occupancy Assay for Covalent Inhibitors.

Hansen Rasmus R Firdaus Sarah J SJ Li Shuangwei S Janes Matthew R MR Zhang Jingchuan J Liu Yi Y Zarrinkar Patrick P PP

Scientific reports 20180925 1

Assessing target occupancy is critical for establishing proof-of-mechanism for novel inhibitors and to determine whether robust target inhibition can be achieved at tolerated doses. This is challenging in the clinic using conventional methods due to the need for untreated controls. We describe a new mass spectrometry approach to quantitatively assess target occupancy for covalent inhibitors that does not require untreated controls, and apply the method to the KRAS<sup>G12C</sup> inhibitor ARS-16 ...[more]

PMID: 30254226

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