TY - JOUR
T1 - Tracking cancer drugs in living cells by thermal profiling of the proteome
AU - Savitski, Mikhail M.
AU - Reinhard, Friedrich B.M.
AU - Franken, Holger
AU - Werner, Thilo
AU - Savitski, Maria Fälth
AU - Eberhard, Dirk
AU - Molina, Daniel Martinez
AU - Jafari, Rozbeh
AU - Dovega, Rebecca Bakszt
AU - Klaeger, Snsan
AU - Kuster, Bernhard
AU - Nordlund, Pär
AU - Bantscheff, Marcus
AU - Drewes, Gerard
PY - 2014/10/3
Y1 - 2014/10/3
N2 - The thermal stability of proteins can be used to assess ligand binding in living cells. We have generalized this concept by determining the thermal profiles of more than 7000 proteins in human cells by means of mass spectrometry. Monitoring the effects of small-molecule ligands on the profiles delineated more than 50 targets for the kinase inhibitor staurosporine. We identified the heme biosynthesis enzyme ferrochelatase as a target of kinase inhibitors and suggest that its inhibition causes the phototoxicity observed with vemurafenib and alectinib. Thermal shifts were also observed for downstream effectors of drug treatment. In live cells, dasatinib induced shifts in BCR-ABL pathway proteins, including CRK/CRKL. Thermal proteome profiling provides an unbiased measure of drug-target engagement and facilitates identification of markers for drug efficacy and toxicity.
AB - The thermal stability of proteins can be used to assess ligand binding in living cells. We have generalized this concept by determining the thermal profiles of more than 7000 proteins in human cells by means of mass spectrometry. Monitoring the effects of small-molecule ligands on the profiles delineated more than 50 targets for the kinase inhibitor staurosporine. We identified the heme biosynthesis enzyme ferrochelatase as a target of kinase inhibitors and suggest that its inhibition causes the phototoxicity observed with vemurafenib and alectinib. Thermal shifts were also observed for downstream effectors of drug treatment. In live cells, dasatinib induced shifts in BCR-ABL pathway proteins, including CRK/CRKL. Thermal proteome profiling provides an unbiased measure of drug-target engagement and facilitates identification of markers for drug efficacy and toxicity.
UR - http://www.scopus.com/inward/record.url?scp=84907485591&partnerID=8YFLogxK
U2 - 10.1126/science.1255784
DO - 10.1126/science.1255784
M3 - Article
C2 - 25278616
AN - SCOPUS:84907485591
SN - 0036-8075
VL - 346
JO - Science
JF - Science
IS - 6205
M1 - 1255784
ER -