Global profiling of cysteine reactivity and ligandability in the human proteome has been performed, making most covalent fragment libraries cysteine-focused, leaving the space of other nucleophilic residues such as serine, threonine, tyrosine, and lysine poorly explored. In addition, the cysteine-targeting covalent fragment hits are often either too reactive in the warhead part or too simple in structure, which poses challenges for further optimization and differentiation. Natural products are a rich source of novel chemotypes and electrophilic moieties but are difficult to access by chemical synthesis. The goal of the proposed research is to simplify and modify the natural products into cov...

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Global profiling of cysteine reactivity and ligandability in the human proteome has been performed, making most covalent fragment libraries cysteine-focused, leaving the space of other nucleophilic residues such as serine, threonine, tyrosine, and lysine poorly explored. In addition, the cysteine-targeting covalent fragment hits are often either too reactive in the warhead part or too simple in structure, which poses challenges for further optimization and differentiation. Natural products are a rich source of novel chemotypes and electrophilic moieties but are difficult to access by chemical synthesis. The goal of the proposed research is to simplify and modify the natural products into covalent fragments while retaining their core scaffold features, thus providing a competitive advantage and constituting predictable success for discovering best-in-class or first-in-class anticancer lead candidates and new ligandable hotspots of therapeutic cancer targets. In Aim 1, using medicinal chemistry, I will build a natural product-derived covalent fragment library. In Aim 2, I will perform a MS-based labeling screening of our covalent fragment library to obtain a biologically active, proteome-wide selective, and metabolically stable lead candidate that covalently labels Cys113 in the PIN1 active site and is suitable for interrogating the anticancer pharmacology of PIN1 inhibition in vivo. In Aim 3, I will perform a MS-based labeling screening of our covalent fragment library to obtain a biologically active, proteome-wide selective, and metabolically stable lead candidate that covalently labels Sec46 in the GPX4 active site and is suitable for interrogating the anticancer pharmacology of ferroptosis induction in vivo. I anticipate that these first-in-class studies will lead to new insights for cancer treatment and serve as an effective research program to launch my independent career as an academic chemical biology scientist at Baylor College of Medicine.

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