Drug discovery and repurposing at Memorial Sloan Kettering Cancer Center: chemical biology drives translational medicine.

Drug discovery and pharmacological research have come a long way since their inception in the mid-19th century. The modern drug discovery pipeline is fairly well established, and an integral component of this streamlined workflow is high-throughput screening (HTS), playing a crucial role in driving the initial stages of “discovery” and laying the foundations for lead optimization. HTS is synonymous to a fishing expedition enabling parallel testing of millions of small molecules or RNA interference (RNAi) duplexes so as to identify novel drugs for therapy or novel molecular targets for diagnostics. Traditionally an expertise exclusive to the pharmaceutical sector, HTS has gradually found its way into academic institutions partly due to reduction in setup costs as well as global initiatives such as the National Institutes of Health (NIH) Roadmap in the USA, encouraging such ventures. Significant advancements in automation, miniaturization, and assay technologies have provoked the emergence of HTS as a prominent paradigm of drug discovery within the past two decades. Therefore, to fuel a rapid discovery of novel targets and drugs for cancer therapy, Memorial Sloan Kettering Cancer Center (MSKCC) opened doors to a High-Throughput Screening Core Facility (HTSCF) in 2003, under the Experimental Therapeutic Center. Since then, it has been instrumental in providing investigator-initiated drug discovery efforts and is equipped with amenities ranging from assay development and optimization to its miniaturization and automation and subsequent follow-up confirmatory studies. 1 HTSCF has been motivated to foster successful collaborations with clinicians and basic researchers so as to provide them with cost-effective HTS solutions to understand complex disease states and to drive innovation. The state-of-the-art robotics, cutting edge instrumentation, innovative high-content assay technologies, and personnel expertise enabled optimal integration of chemical biology and functional genomics approaches conducive to adoption on a high-throughput platform. The probes discovered from large-scale screens would be further used to investigate key signaling pathways or interrogated for hit to lead transformation and eventually drug development. Translational medicine is arising as a contemporary discipline of drug discovery. With this foresight, the US Food and Drug Administration (FDA)-approved drugs made up an integral part of our diverse chemical collections for screening. This has presented an exciting opportunity to repurpose old drugs for newer treatments, opening avenues to rapidly transition drugs from laboratory to clinic, a critical achievement toward addressing unmet clinical needs, and with direct impact on patient care (Figure 1). Besides drug repurposing efforts and novel inhibitor identification for lead generation, a broadspectrum brute force approach is also undertaken to elucidate novel pathways for therapeutic intervention, to study genetic abnormalities among nonresponder populations, for biomarker discovery, and to explore drugs for combination therapy. In this report, we discuss the fundamentals of academic screening as a means to discover drugs for clinical use through the lens of the HTSCF.