Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, driven by the BCR-ABL1 fusion oncoprotein. The discovery of orthosteric BCR-ABL1 tyrosine kinase inhibitors (TKIs) targeting its active ATP-binding pocket, such as first-generation Imatinib and second-generation Nilotinib (NIL), has profoundly revolutionized the therapeutic landscape of CML. However, currently targeted therapeutics still face considerable challenges with the inevitable emergence of drug-resistant mutations within BCR-ABL1. One of the most common resistant mutations in BCR-ABL1 is the T315I gatekeeper mutation, which confers resistance to most current TKIs in use. To resolve such conundrum, co-administration of orthosteric TKIs and allosteric drugs offers a novel paradigm to tackle drug resistance. Remarkably, previous studies have confirmed that the dual targeting BCR-ABL1 utilizing orthosteric TKI NIL and allosteric inhibitor ABL001 resulted in eradication of the CML xenograft tumors, exhibiting promising therapeutic potential. Previous studies have demonstrated the cooperated mechanism of two drugs. However, the conformational landscapes of synergistic effects remain unclear, hampering future efforts in optimizations and improvements. Hence, extensive large-scale molecular dynamics (MD) simulations of wide type (WT), WT-NIL, T315I, T315I-NIL, T315I-ABL001 and T315I-ABL001-NIL systems were carried out in an attempt to address such question. Simulation data revealed that the dynamic landscape of NIL-bound BCR-ABL1 was significantly reshaped upon ABL001 binding, as it shifted from an active conformation towards an inactive conformation. The community network of allosteric signaling was analyzed to elucidate the atomistic overview of allosteric regulation within BCR-ABL1. Moreover, binding free energy analysis unveiled that the affinity of NIL to BCR-ABL1 increased by the induction of ABL001, which led to its favorable binding and the release of drug resistance. The findings uncovered the in-depth structural mechanisms underpinning dual-targeting towards T315I BCR-ABL1 to overcome its drug resistance and will offer guidance for the rational design of next generations of BCR-ABL1 modulators and future combinatory therapeutic regimens.

A simple ratiometric sensor (L1) for the cascade detection of Zn²⁺ and H₂PO₄⁻ with high selectivity was reported based on the intermolecular charge transfer (ICT) mechanism.

Biological channels in the cell membrane play a critical role in the regulation of signal transduction and transmembrane transport. Researchers have been committed to building biomimetic nanochannels to imitate the above significant biological processes. Unlike the fragile feature of biological channels, numerous solid nanochannels have aroused extensive interests for their controllable chemical properties on the surface and superior mechanical properties. Surface functionalization has been confirmed to be vital to determine the properties of solid nanochannels. Macrocyclic hosts (e.g., the crown ethers, cyclodextrins, calix[n]arenes, cucurbit[n]urils, pillar[n]arenes, and trianglamine) can be tailored to the interior surface of the nanochannels with the performance of stimuli response and separation. Macrocycles have good reversibility and high selectivity toward specific ions or molecules, promoting functionalies of solid nanochannels. Hence, the combination of macrocyclic hosts and solid nanochannels is conducive to taking both advantages and achieving applications in functional nanochannels (e.g., membranes separations, biosensors, and smart devices). In this review, the most recent advances in nanochannel membranes decorated by macrocyclic host–guest chemistry are briefed. A variety of macrocyclic hosts-based responsive nanochannels are organized (e.g., the physical stimuli and specific molecules or ions stimuli) and nanochannels are separated (e.g., water purifications, enantimerseparations, and organic solvent nanofiltration), respectively. Hopefully, this review can enlighten on how to effectively build functional nanochannels and facilitate their practical applications in membrane separations.