Development of Novel Autophagy Modulators to Improve the Sensitivity of Oral Squamous Cell Carcinoma to Chemotherapy

Project 1: “Development of novel autophagy modulators to improve the sensitivity of oral squamous cell carcinoma to chemotherapy.” Oral squamous cell carcinoma (OSCC) is the predominant malignant neoplasm in the oral cavity. The major challenges in OSCC lie in the late-stage diagnosis, scarcity of therapeutic strategies, and the development of drug resistance during the anti-tumor therapy. Autophagy is a lysosome-dependent catabolic mechanism to maintain the cellular homeostasis in eukaryotic cells by degrading and recycling the cytoplasmic components. Autophagy can offer an alternative metabolic pathway to the cells when the regular energy sources are compromised. Till date, almost all class of anti-cancer compounds in clinical trials has been associated with autophagy-mediated drug resistance. Additionally, the inhibition of autophagy has been demonstrated as therapeutic benefit. However, the clinical trials with autophagy inhibitors like chloroquine and hydroxychloroquine have produced several drawbacks like severe toxic effects and higher dose requirement. Pyrrolobenzoxazepines (PBOXs) and Pyrrolonaphthoxazepines (PNOXs) have been characterized as a colchicine-binding, microtubule network disrupting anti-cancer agents. They can exhibit their pro-apoptotic potential in a wide range of tumor cell lines, including, OSCC with minimal toxicity. PBOX-6 was able to induce autophagy in colon adenocarcinoma cell lines. Henceforth, we have synthesized novel analogs with newly developed synthetic strategies to evaluate the role of autophagy in the efficacy profile of the PBOXs/PNOXs in OSCC. In our delight, two of the best performing compounds with a promising drug-like profiling, have been characterized as autophagy inhibitors in OSCC and HL-60 cell lines. We expect that this study will shed light on the chemical features that are responsible for governing autophagy modulation by PBOXs/PNOXs. Project 2: "Development of new β-lactam based HDAC6 inhibitors as anticancer agents". Histone deacetylases (HDACs) are a regulator in chromatin remodelling and genetic expression. HDAC upregulation has been observed in several cancer developments. Therefore, the inhibition of HDACs has evolved as a pharmacological target for specific epigenetic modifications in cancer research. HDAC6, a selective isoenzyme symbolizes an important target for selective inhibition over the pan-HDAC inhibitors with reduced toxicity. HDAC6 inhibition has been reported to be beneficial in preclinical and clinical studies. The β-lactam family has been used for many years to treat bacterial infections. Interestingly, β-lactams have also been explored for selective HDAC inhibition by several research works. We focused on the development of selective HDAC6 inhibitors, with a β-lactam core structure. After performing a molecular modeling approach, we designed a series of compounds with different caps groups and linkers, keeping hydroxamic acid as a common zinc binding group. The newly developed structures were inspired by the scaffold of a previously developed inhibitor identified by our research group. All the compounds have been tested for the inhibitory effect on both the HDAC1 and HDAC6 isoforms. The best compound showed an IC50 value of 3.4 nM on HDAC6 with 1265-fold selectivity compared to the HDAC1 isoform.