A paucity of advances in the development of novel therapeutic agents for squamous cell carcinomas of the head and neck, oral cavity (OSCC) and oropharynx, has stagnated disease free survival rates over the past two decades. Although immunotherapies targeted against checkpoint inhibitors such as PD-1 or CTLA-4 are just now entering the clinic with regularity, the well-known CheckMate14 reported a median overall survival of 7.5 months vs 5.1 months on the control arm. There is an urgent unmet clinical need to identify new therapies that can be used alone or in combination with current approaches to increase survival by more than a few months. Activation of the apoptotic arm of the unfolded response (UPR) with small molecules and natural products has recently been demonstrated to be a productive approach in pre-clinical models OSCC and several other cancers. The aim of current study was to perform a high throughput screen (HTS) with a diverse chemical library to identify compounds that could induce CHOP, a component of the apoptotic arm of the UPR. Acetyl Isogambogic Acid (AIGA), a natural product derived from several species of indigenous Asian evergreens, emerged as a hit that could induce ER stress, the UPR and apoptosis in a panel OSCC cells in culture. Murine embryonic fibroblasts and OSCC cells that were CHOP- null were resistant to AIGA suggesting that an intact UPR is a key element of the mechanism regulating the antiproliferative effects of AIGA.