DiscussionConventional small-molecule discovery approaches are both time consuming and resource inefficient. These approaches involve the synthesis, purification and screening of many individual molecules, using a limited palette of reliable and well-established chemical transformations. Hence, all molecules are treated with the same significance irrespective of their ultimate biological activity. We present a novel evolutionary approach which is highly efficient and focuses only on active compounds: sequential rounds of promiscuous carbenoid reactions, screening of unpurified reaction mixtures and selection of the most productive conditions, lead to the rapid discovery of small-molecule modulators of a known biological target, based on a novel scaffold.3 The approach allows for the parallel optimisation of both the structure of the bioactive molecule and a route for its synthesis. Sub-micromolar, chemically unprecedented and biologically novel modulators of a known biological target have been discovered using this newly developed methodology.