My laboratory focuses on applying chemistry-based approaches to propel the development of molecular and cellular modalities for various disorders. I will briefly introduce our efforts in cellular engineering using CRISPR-based technologies and the development of zinc-based prodrug systems and then focus on Phosphorylation-Inducing Chimeric Small molecules (PHICS). Small molecules have been classically used to inhibit enzyme function (i.e., loss-of-function), but several new classes of small molecules are emerging that endow neo-functions to enzymes via proximity-mediated effects. I will describe the development and applications of PHICS, which can induce the phosphorylation of a given target protein by forcing proximity between a kinase and the target protein. Platform development: The first-generation PHICS were formed by joining the target binder via a linker to a non-inhibitory kinase binder, which is scantily available. I will describe linkers based on addition-elimination reactions that enable the generation of PHICS using kinase inhibitors (abundantly available), allowing rapid development of PHICS for &gt; 30 kinases (and their isoforms). Beyond PHICS, these linker chemistries may accelerate the development of chimeric molecules that induce/remove other post-translational modifications. Novel bioactivities of PHICS: I will describe various activities of PHICS, including induction of phosphorylations that trigger signal transduction events and installation of neo-phosphorylations (unobserved endogenously and potentially immunogenic) that adversely affect the target protein’s ability to interact with negatively charged biomolecules. For example, PHICS-mediated phosphorylation disrupted the ability of KRAS, a GTPase that translocates to the membrane, to interact with GTP/phospholipids. “Homo-PHICS” (i.e., a dimer of kinase binder) efficaciously inhibited the kinase by inducing ATP-binding pocket’s phosphorylation that disrupts further ATP loading. This novel mechanism of action allowed PHICS to efficaciously kill cancer cells resistant to known drugs (e.g., Imatinib/Asciminib for CML, Ibrutinib for CLL). Overall, these studies lay the foundations for a novel therapeutic modality for cancer and demonstrate the power of synthetic chemistry to expand the chemical and functional diversity of proteins in cells using chimeric molecules.

Chemical approaches to genome and protein editing

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ACS Spring 2023

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