Executive Summary : | Objective: 1. a. Synthesis of large quantity of the lead molecule and Chemistry, Manufacturing & Control (CMC) 2. Pharmacokinetics / Toxicokinetics analysis: Oral and intravenous comparative pharmacokinetics studies and tissue distribution, bio availability and BBB studies of lead molecule identified 3. In vivo toxicity - Maximum Tolerable dose in mice (MTD), repeated dose toxicity study in mice with hematology, clinical biochemistry and histopathology 4. In vitro and In vivo ADME studies – plasma protein binding, metabolic stability, CYP liability (inhibition) and hERG study. 5. General toxicology and Genotoxicity of the identified lead molecule for IND application Summary: Though chemotherapy agents are in use for treatment of pancreatic and renal cell cancer, emerging resistance and targeting late stage tumor is of major concern and therapy response is limited. Hence, treatment of pancreatic and renal cell cancer is still unmet medical need. Therefore, a natural product nimbolide based NCE that is highly potent anti cancer agent against pancreatic and renal cell cancers has been developed. The potential of the lead molecule was assessed against cells derived from pancreatic and renal cancer patients (ex vivo study). In vivo efficacy data in mouse tumor models determined translation potential of the lead. Further acute toxicity studies in BALB/c mice highlights its favorable therapeutic index and emphasizes potential to determine pharmacological properties and perform preclinical studies with the lead compound (Patent filed, Application no: 201811000561, Date: 05.01.2018, Nimbolide derivatives as potential anti-cancer agents). Therefore, here it is proposed to carryout systematic IND enabling studies for cataloguing the drugable parameters of the lead molecule for its clinical development by entering into licensing agreement with pharma industry eventually to mature a pharmaceutical product. |