Intrahepatic cholangiocarcinoma (ICC) is a rare and aggressive form of biliary tract cancer. Standard of care chemotherapy for patients with unresectable, recurrent, or metastatic biliary tract cancer is systemic treatment with nucleoside analogs such as capecitabine and gemcitabine in combination with platinum complexes such as cisplatin and oxaliplatin (). Median survival following diagnosis remains less than a year. The search for dominant molecular alterations that may play a critical role in driving tumorigenesis has revealed that mutations within the isocitrate dehydrogenase genes 1 and 2 (IDH1/2) are often present in ICC that are refractory to chemotherapy. To find synthetic lethal sensitivities present in cells harboring IDH1/2 mutations, we executed a systematic highthroughput screen of approved and experimental therapeutics libraries to identify compounds that selectively kill ICC cell lines harboring IDH1 mutations. To that end, a collection of 7,988 compounds with annotated mechanisms of action and/or pharmacological targets was screened in 8-point dose response against the RBE and SNU-1079 biliary tract cancer cell lines that contain the common R132H and R132C IDH1 mutations, respectively. Counter-screening against biliary tract cell lines CCLP1 and HUCCT1 containing wild type (wt) IDH1 was done to deprioritize cytotoxic compounds towards cells with wt IDH1. A top-ranked compound that emerged from these screening efforts was 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1; lificiguat), window tested. The percentage reduction of the CellTiter-Glo™ signal at the highest concentration tested (46 M) is also reported. Table delineates our focus on the furfuryl alcohol region. We found that the methylene alcohol adjacent to the furan was essential for cellular potency, as one carbon extension to homobenzylic alcohol 2, capping the alcohol as its methyl ether 3, or complete removal of the hydroxyl group (4) led to dramatic declines in activity. Furthermore, introducing a substituent at the methylene position, such as methyl or cyclopropyl in analogs 5 and 6, respectively, led to significantly reduced potency. We then took a systematic approach to explore the furan attempting to replace it with more metabolically stable heteroarenes. The potency of these analogs was found to be sensitive to even minor modifications in this region. For instance, introducing an additional nitrogen to the furan, as shown in oxazoles 7, 8, and 9, eroded activity with <50% inhibition even at the highest concentration tested. Similarly, replacing the furan with a thiophene, phenyl, or saturated tetrahydrofuran in compounds 10, 11, and 12 was equally detrimental to compounds' activities.