New chemical biology tools to explore the beyond-rule-of-5 drug space
There is an increasing need to pursuit less druggable targets that offer high potential for the development of new therapeutic agents and may require beyond-rule-of-5 (bRo5) molecules in order to take advantage of these opportunities. Nevertheless, bRo5 chemical space remains relatively unexplored, most likely due to the perceived non-oral properties, increased complexity of compounds in this space and the synthetic chemistry challenges associated with its navigation. There is a pressing need to develop new technologies for the discovery and oral delivery of bRo5 drugs. We will develop new chemical biology approaches that enable phenotypic screening of large, de novo bRo5 compound libraries inside living cells. Such efforts could potentially yield novel hits for “undruggable” targets in cancer therapeutics. The strategies used here will be further pursued for applications in oral delivery of bRo5 compounds.
Affecting protein stability as a new strategy to target KRAS
The Kirsten rat sarcoma viral oncogene homologue (KRAS) gene is one of the most frequently mutated oncogenes in cancer. KRAS is mutated in ∼30% of human cancers and is one of the most sought-after targets for pharmacological modulation. Despite its well-recognized importance in cancer malignancy, continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. Recent efforts in direct targeting KRASG12C have resulted in small molecule inhibitors that showed great promise in early clinical trials. However, G12C mutant only represents a small percentage of patients with oncogenic KRAS mutations. To explore a general strategy to target KRAS, we will combine chemical screen and genetic screen to identify small molecules and genes that can destabilize KRAS across different mutant KRAS cell lines. Results from these screens will provide novel therapeutic leads and mechanistic insights of KRAS degradation pathway. Leveraging these findings, we hope to develop next-gen small molecule therapeutics for the treatment of KRAS mutant cancer.
New tools for live-cell protein labeling and super-resolution imaging
Proteins are the essential components in cell function. To understand the function of proteins in living cells, it is important to know the properties of proteins in the temporal and spatial context of the cell. Currently, live-cell protein labeling and imaging technologies have several limitations: 1) Widely adopted tools for live-cell protein labeling have a large size (20-30kDa), giving rise to concerns that they may interfere with protein folding, trafficking, activity, and interactions; 2) Fluorescence proteins or small molecule dyes bleach quickly under super-resolution imaging conditions, thus prevent long-term protein imaging. To solve these problems, we will develop short peptide tags for site-specific protein labeling in live cells. Such tags contain only a few amino acids and will have minimal perturbation of protein function. We will also develop photo-bleaching-resistant live cell protein imaging tools that allow biologists to visualize the dynamics of proteins at the nanoscopy level (resolution<50 nm) with unlimited “photon budget”.
We are an interdisciplinary research group working at the interface of chemistry and biology. Students in the lab will receive multidisciplinary training in experimental techniques ranging from synthetic chemistry to fluorescence microscopy to cellular studies. Representative skill sets in the group are given below.
- Chemical tools: organic synthesis, catalysts, medicinal chemistry, peptide synthesis
- Cell culture: mammalian cell lines, primary cell cultures
- Cell imaging: Confocal microscopy, STED, single molecule microscopy, flow cytometry
- Molecular biology: Cloning, PCR, CRISPR
- Biochemistry: Protein purification, western blotting