Tracking cancer drugs in living cells by thermal profiling of the proteome

TLDR

Mapping drug targets in cells is essential to understand therapeutic benefits and side effects, as illustrated by the photosensitivity of the cancer drugs vemurafib and Alectinib. The study aims to take significant steps toward meeting the daunting challenge of mapping drug targets in cells. The authors monitored the unfolding of over 7,000 human proteins and measured how small‑molecule binding alters each protein’s melting profile. The approach identified over 50 targets for a broad‑spectrum kinase inhibitor and revealed drug–protein interactions underlying the photosensitivity side effects. Savitski et al., Science, 10.1126/science.1255784.

Abstract

Mapping human drug targets in the cell To understand both the beneficial and the side effects of a drug, one would need to know its full binding profile to all cellular proteins. Savitski et al. take significant steps toward meeting this daunting challenge. They monitored the unfolding or “melting” of over 7000 human proteins and measured how small-molecule binding changes individual melting profiles. As a proof of principle, over 50 targets were identified for an inhibitor known to bind a broad spectrum of kinases. Two cancer drugs, vemurafib and Alectinib, are known to have a side effect of photosensitivity. The thermal profiling approach identified drug-protein interactions responsible for these side effects. Science , this issue 10.1126/science.1255784