Discovery of a miniaturized PROTAC with potent activity and high selectivity.

The approved small-molecule inhibitors of anaplastic lymphoma kinase (ALK) have shown remarkable efficacy in some subset of cancer patients. However, the numerous ALK mutants or fusion partners are resistant to such drugs, greatly limiting their application in clinic. Despite the drug design strategy of proteolysis-targeting chimera (PROTAC) holds great potential to overcome drug resistance in theory, there are obvious disadvantages for the reported PROTACs that include high molecular weight, long linkers, difficult synthesis routes as well as insufficient evidence in activity for diverse ALK mutants. In this study, we designed and synthesized a miniaturized PROTAC of ALK named AP-1 following the principle of minimalist design. Two simple chemical units of ligands and a minimized linker with only two atoms were selected for synthesis of AP-1. At cellular level, AP-1 successfully degraded three types of ALK mutants including NPM-ALK, EML4-ALK and F1174L mutation ALK form with potent activity, high selectivity in ALK-positive cells. In xenograft mouse model, AP-1 showed the stronger antitumor efficacy than ceritinib as well as ALK degraders reported in literatures. AP-1 with an extremely simple PROTAC structure can be served as an effective candidate drug for therapy of various types of ALK-positive cancers. And the design principle of AP-1 has a good guiding significance for overcoming the disadvantages such as excessive molecular weight and poor solubility of PROTAC.

Polymeric Nanoreactors with Chemically Tunable Redox Responsivity.

Bioresponsive nanomaterials are increasingly important in a variety of applications such as disease imaging, drug delivery, and tissue engineering. However, it remains a big challenge to manipulate response efficacy of such materials for performance optimization in a highly complex milieu in vivo. Here, we developed chemically adjustable nanoreactors (CANs) with the structure of polymeric cores and albumin shells to achieve tunable redox responsivity. In vitro characterization demonstrates stable, spherical nanoparticles of the CANs with a particle size of about 50 nm. The fluorescence activation ratios of the CANs are determined by various albumin modification densities on the shell. Meanwhile, the response sensitivity of the CANs to GSH levels (0.6-4 mM) can be tuned by acid-base properties of polymeric blocks in the core. This unique tunable redox responsivity enables the CANs suitable for probe optimization in cancer imaging both in vivo and at histological levels. Overall, this study offers a new design strategy for manipulation on performance of core/shell nanoreactors or bioresponsive nanomaterials.