PROJECT SUMMARY Therapeutic approaches in cancer therapies have evolved from the use of highly toxic chemotherapy agents to precision medicine with well-defined targets and minimal toxicities. While precision medicine is highly desirable, its effectiveness depends on the presence of the activating agents and typically target a single pathway which is conducive to the development of drug resistance when alternative pathways and or feedback mechanisms are used. These limitations are best exemplified by anti-cancer therapies targeting the protein translation regulator mammalian Target Of Rapamycin (mTOR). Although these inhibitors show clear benefit in some cancers such as mantle cell lymphomas, Renal Cell Carcinoma and Tuberous Sclerosis Complex-related tumors they have limited efficacy as single agents in most other cancers due to compensatory feedback mechanisms. In addition, targeting components of the general protein translational machinery that are also essential for normal cell functions would likely contribute to normal tissue toxicity. Agents that could target simultaneously a number of limited key pathways essential for cancer cells progression and survival would thus be expected to decrease toxicity and resistance. To this Aim we have identified first in class small molecule inhibitors of hnRNP A18, a regulator of protein translation in cancer cells. hnRNP A18 targets transcripts that are involved in cancer progression, metastasis, angiogenesis, anti-apoptosis and tumor immune checkpoint. Our working hypothesis is that small molecule inhibitors of hnRNP A18 will inhibit the translation of specific RNA transcripts devoted to conferring growth advantages and immune protection to cancer cells. To verify this hypothesis three complementary specific Aims have been designed: Aim 1: Design, synthesize and improve small molecule inhibitors of hnRNP A18. Aim 2: Prioritize compounds through in vitro methods including RNA binding, cell reporter assay, proliferation and toxicity. Aim 3: Determine in vivo anti-tumor and ADMET properties of lead compounds, employing, xenograft, syngeneic and Patients Derived (PDX) tumors models. A multidisciplinary team of experts composed of medicinal chemists, structural biologist, theoretical chemists, cancer biologist, immunologist and an oncologist has been assembled to develop and optimize this new class of anticancer agents with the ultimate goal of bringing them into the clinic.