Most drugs work not only by engaging a single target, but by producing large, complex perturbations of biological systems. In general, the expectation is that the systematic adoption of more rigorous and “systems-level” characterization of chemical entities will help understanding the biology of drug action better and allow the development of improved drugs. It should help the community in rationalizing patient stratification, thus increasing the efficacy of clinical trials and reduce unwanted side effects, but also contribute to the employment of mechanism-based combination therapy with existing drugs.
Drug target identification, drug synergies and mechanisms of drug resistance
Historically, the lab has identified new targets for known drugs, previously unknown mechanisms of drug resistance, “effector” genes for the compounds (genes required for the drug to exert its action), mechanisms of synergy between compounds (Winter et al, Nature Chemical Biology, 2012) and, in a few cases, new medical use of existing drugs. By investigating existing drugs with unclear mode of action on rapidly dividing cancer cells and using its arsenal of innovative technologies to uncover their molecular mechanism, the Superti-Furga laboratory has recently identified a new drug target in a poorly characterized pathway involved in the metabolism of oxidized nucleotides (Huber et al, Nature 2014).
The Superti-Furga laboratory has developed or adapted a variety of chemical biology approaches such as chemo-proteomics, genome editing and haploid genetic screens to understand drug action at the molecular level. The laboratory has also developed a small molecule interaction mapping technology using mass spectrometric thermal stability shifts at the proteome-wide level, allowing to investigate the impact of any molecule on intact cells on a global scale (Huber et al, Nature Methods, 2015).