Identification of small molecule inhibitors for IDH1

One of the first differences described between cancer and normal cells was a difference in metabolism. Cancer cells uniquely and effectively convert nutrients into cellular building blocks, such as lipids and proteins, to support their survival and expansion. My laboratory identified isocitrate dehydrogenase-1 (IDH1) as a critical metabolic enzyme that is commonly overexpressed in different tumor types compared to non-cancerous tissue. Through in-depth molecular studies, we discovered that IDH1 promotes cancer progression and therapy resistance by increasing the capacity of tumors cells to produce lipids and cell protective anti-oxidants. In collaboration with SAMDI Tech, using their proprietary mass spectrometry approach, we screened a 100,000 compound library to identify small molecule compounds that potently inhibit IDH1 enzymatic activity. We identified a group of 7 compounds that inhibit IDH1 activity in cell-free systems. Figure 1 shows the most potent compound (NU-841) that can inhibit 50% IDH1 enzymatic activity at low concentration (Inhibitory Concentration 50 (IC50) is excellent and in the low µM range).