The proposed research program aims to accelerate drug discovery in cancer by developing enabling technologies for therapeutic targeting of ribonucleoprotein (RNP) complexes regulating mRNA translation and availability in stress response of cancer cells. RNP granules form cytoplasmic membraneless condensates to compartmentalize and concentrate cellular processes that facilitate survival of cancer cells in the tumor microenvironment and mediate resistance to anticancer treatments. The unique composition and dynamics of RNPs and how these molecular features of RNA granules are regulated to promote cancer cell adaptation and progression remains poorly understood. The overarching hypothesis is th...

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The proposed research program aims to accelerate drug discovery in cancer by developing enabling technologies for therapeutic targeting of ribonucleoprotein (RNP) complexes regulating mRNA translation and availability in stress response of cancer cells. RNP granules form cytoplasmic membraneless condensates to compartmentalize and concentrate cellular processes that facilitate survival of cancer cells in the tumor microenvironment and mediate resistance to anticancer treatments. The unique composition and dynamics of RNPs and how these molecular features of RNA granules are regulated to promote cancer cell adaptation and progression remains poorly understood. The overarching hypothesis is that disruption of interactions between RNA-binding proteins (RBPs) and RNA through covalent binding of tyrosines in RNA-recognition domains will enable pharmacology of RNP function in cancer. To address this question, a multidisciplinary approach leveraging SuTEx chemistry developed in the Hsu Lab will be deployed for therapeutic investigation of cancer-relevant RNPs. Specifically, targeted covalent inhibitors against enhancer of mRNA decapping protein 3 (EDC3) will be developed to investigate the druggability of this putative RBP for controlling cancer RNPs (Aim 1). A streamlined phenotypic screening-chemical proteomic target identification strategy will be deployed for rapid and proteome-wide discovery of covalent small molecule modulators of cancer RNPs with a defined mechanism of action (Aim 2). Patient-derived xenografts will be integrated into the discovery platform to gain molecular insights into RBP activity changes in response to the clinical environment and chemotherapy in order to furnish new drug targets for precision medicine in oncology (Aim 3). The overall impact of the proposed research is a creative means to reveal and drug tumor-specific stress coping mechanisms found in dynamic cellular compartments for precision medicine in oncology.

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