This project aims at identifying novel chemical compositions for potent anaplastic lymphoma kinase (ALK) inhibitors as the next-generation therapy for nonsmall cell lung cancer (NSCLC). ALK inhibition has considerably improved therapeutic outcomes in the treatment of ALK positive cancers. Unfortunately, mutation-based resistance emerges rapidly. Currently, small molecule drugs on the market are all type-I inhibitors that bound to the ATP-binding pocket and are most likely to be resistant in patients harboring genetic mutations surrounding the ATP pocket. To overcome drug resistance, we are developing a novel bridge inhibitor, which specially binds into an extended hydrophobic back pocket adjacent to the ATP-binding site of ALK. The novel type-I1/2 inhibitors display excellent antiproliferation activity against ALK-positive cancer cells and appear superior to two clinically used drugs, crizotinib and ceritinib. Our continuing efforts in this project focuses on exploring detailed structure activity relationships (SAR) and improving pharmacokinetics. We are hoping that leading candidates out of this project will demonstrate excellent efficacy in xenograft mouse models with good drug-like properties.
Safety training is required (MC03 Chemical Safety II and MC07 Chemical Safety I).
Training for use of departmental instruments is required (NMR, LC-MS, GC-MS).
The applicants are expected to perform intensive synthetic chemistry experiments. They will be guided by a senior group member on performing various organic reactions and isolating products. They will use analytic instruments independently to confirm the structure and purity of those products.
1. Able to performing multi-step organic transformations.
2. Able to understand basic mechanisms of various organic reactions.
3. Able to use common analytic instruments for structure elucidation and purity assessment.
3. Acquire basic level of SAR analysis for medicinal chemistry.