Chemical biology and therapeutics science has evolved rapidly over the past decade. CBTS is leveraging — and in many cases driving:
- breakthroughs in the use of macromolecules to study biology and modify the genome and proteome in therapeutically relevant ways;
- development of technologies to explore the small-molecule and macromolecular structure space and rapidly identify molecules with remarkable biological properties;
- innovative means of using chemistry to provide an unprecedented view of previously unseen processes in living systems.
These efforts combine with disease-focused research conducted by Broad scientists to find therapeutic solutions to the biological challenges posed by human disease.
Innovation in chemistry and drug discovery
- Computational method development: CBTS researchers are developing systematic computational approaches to small-molecule science, seeking to describe similarity and diversity of small molecules and small-molecule collections in terms of their measured performance in biological settings, and to find computational descriptions of small-molecule structure that correlate with and predict performance.
- Continuous directed evolution of macromolecules: Members of CBTS have harnessed the life cycle of the filamentous bacteriophage to develop phage-assisted continuous evolution (PACE), a system for the continuous directed evolution of proteins and nucleic acids. PACE allows researchers to rapidly evolve new activities in macromolecules with minimal intervention, potentially providing solutions to otherwise intractable directed-evolution problems and addressing novel questions about molecular evolution.
- DNA-templated synthesis (DTS): CBTS researchers are exploring the ability of DTS — which enables selection, amplification, and mutation to be applied to molecules that can only be accessed through chemical synthesis — to translate DNA sequences into synthetic molecules. Recent efforts in DTS have led to the discovery of several bioactive molecules as well as three new chemical reactions.
- Macromolecular delivery via "supercharged" proteins: Delivery of macromolecules that can alter genomes, transcriptomes, or proteomes while preserving their activities and minimize the risk of undesired side effects remains a barrier to a) precise manipulation of the flow of information within cells, and b) the use of proteins and nucleic acids as intracellular probes and therapeutic agents. CBTS members are exploring proteins with altered surface charges (e.g., superpositively charged proteins) as a way to potently and efficiently deliver enzymes, siRNAs, and plasmid DNA into cells.
- Mechanism-of-action studies: Target identification and mechanism-of-action (MoA) studies are largely ad hoc, slow, laborious, and do not always result in successful outcomes. CBTS researchers are developing a systematic approach to MoA discovery that rapidly incorporates data from multiple sources, enabling rapid prioritization of small molecules and potentially reducing the costs associated with library screening and structure-activity relationship optimization.
- Nucleic-acid structure and function discovery: Many RNAs are now known to play a wide range of catalytic, regulatory, or defensive roles in the cell. CBTS researchers are screening for and interrogating small molecule—RNA conjugates in microbial and eukaryotic cells, revealing that the chemical diversity of biological RNA in modern cells is greater than previously understood.
- Small-molecule profiling: Small-molecule profiling experiments can reveal the outcomes of a small molecule's activity on different cell types or cell states. CBTS is pioneering methods that allow researchers to investigate the possible targets of novel small molecules based on cell-based assays and by connecting synthesis steps and molecular performace.
- Synthetic chemistry: CBTS aims to support drug discovery and transform the role of chemists in the earliest stages of drug discovery by focusing on compound collections' diversity in biological performance, as opposed to chemical diversity—a critical parameter for improving the ability of high-throughput screens to identify hits based on diverse biological targets and cellular phenotypes.
- Cancer biology: CBTS researchers are engaged in several collaborative projects with the Broad Cancer Program aimed at identifying and translating biological insights into potential cancer therapeutics.The Cancer Therapeutics Response Portal (CTRP), for example, is a growing resource for identifying drug-targetable dependencies created by specific genomic alterations within human cancers. We are also probing epigenetic mechanisms in cancer, seeking opportunities to target chromatin-modifying proteins in ways that affect oncogene regulation, inheritance of chromatin states, and cellular development.
- Circadian biology: Sleep and circadian rhythms play hitherto unappreciated roles in human health and disease. CBTS teams are collaborating on genetic and mechanistic studies of candidate genes identified in human genome-wide association studies, as well as projects aimed at identifying small molecules that can perturb circadian biology for use as chemical probes.
- Metabolic disease: CBTS are actively seeking compounds that could achieve the goal restoring glycemic control in type 1 or type 2 diabetes. These efforts include development of phenotypic-cell-based assays to find compounds that can affect different aspects of beta-cell biology (e.g., increase proliferation, protect from inflammatory processes) or induce beta-cell transdifferentiation. CBTS researchers are also collaborating with the Slim Initiative for Genomic Medicine for the Americas Type 2 Diabetes (SIGMA-T2D) Consortium to leverage the consortium's genetic findings to identify novel lead compounds for tool use and therapeutic development.
- Microbial Therapeutics: Malaria and tuberculosis (TB) remain two of the world's leading infectious threats. Starting with hits derived from diversity-oriented synthesis, CBTS, working with the Broad Infectious Disease Program, are advancing compounds demonstrating activity against multiple stages of the malaria parasite life cycle. Simultaneously, the we are working to improve the potency and pharmacokinetics of compounds acting against unique targets in TB.
- Prion disease and neurodegeneration: The foundational mechanism of prion diseases—pathologic accumulation of misfolded proteins—has been recognized as a model for a diverse grouping of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. CBTS, together with researchers in the Stanley Center for Psychiatric Disease Research, is using cell-based models and molecular screens to identify compounds with therapeutic potential for human prion diseases, as well as small molecules that target ApoE4, an allele strongly associated with Alzheimer's disease.