Recent progress in degradation of membrane proteins by PROTACs and alternative targeted protein degradation techniques.

Targeted protein degradation (TPD) is one of the key strategies of current targeted cancer therapy, and it can eliminate some of the root causes of cancer, and effectively avoid drug resistance caused by traditional drugs. Proteolysis targeting chimera (PROTAC) is a hot branch of the TPD strategy, and it has been shown to induce the degradation of target proteins by activating the inherent ubiquitin-proteasome system (UPS) in tumor cells. PROTACs have been developed for more than two decades, and some of them have been clinically evaluated. Although most of the proteins degraded by PROTACs are intracellular, degradation of some typical membrane proteins has also been reported, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), programmed death ligand 1 (PD-L1), and G-protein-coupled receptor (GPCR). In addition, some other effective membrane protein-degrading strategies have also emerged, such as antibody-based PROTAC (AbTAC), lysosome targeting chimera (LYTAC), molecular glue, and nanoparticle-based PROTAC (Nano-PROTAC). Herein, we discussed the advantages, disadvantages and potential applications of several important membrane protein degradation techniques. These techniques that we have summarized are insightful in paving the way for future development of more general strategies for membrane protein degradation.

Solvatomorphism and first-time observation of acid-acid catemer in 4-phenylamino-benzoic acids.

To investigate the polymorphism in 4-phenylamino-benzoic acids (4-PABAs) in general, and the effect on the polymorphism of these compounds exerted by substitution in particular, a series of 4-PABAs (1-8) varying in the substitution position and pattern were synthesized, and their polymorphic behavior was investigated for the first time. A relatively comprehensive polymorph screening led to the discovery of two forms, one solvent-free and the other solvate, for compounds 1, 3 and 8, and one form for the other compounds. The crystal structures were determined by single-crystal XRD. All the 4-PABAs in the crystal structures are highly twisted, and all the solvent-free crystals are based on the conventional acid-acid dimer motif, except for 2, which has a rarely observed acid-acid catemer motif. Two of the solvates (1-S and 8-S) have pyridine in the lattice while the other (3-S) has dichloromethane. The observation indicates that neither conformational flexibility or substitution alone nor the combination of both leads to polymorphism in these compounds, which is in dramatic contrast to the polymorphism of fenamic acids. The thermal properties of each system were investigated by differential scanning calorimetry and desolvation of the solvates was studied by thermogravimetric analysis. Hirshfeld surface analysis and molecular dynamics simulation were performed to study the mechanism of polymorphism and the intermolecular interactions contributing to the formation and stability of each crystal form.