Structure-Based de Novo Molecular Generator Combined with Artificial Intelligence and Docking Simulations.

Recently, molecular generation models based on deep learning have attracted significant attention in drug discovery. However, most existing molecular generation models have serious limitations in the context of drug design wherein they do not sufficiently consider the effect of the three-dimensional (3D) structure of the target protein in the generation process. In this study, we developed a new deep learning-based molecular generator, SBMolGen, that integrates a recurrent neural network, a Monte Carlo tree search, and docking simulations. The results of an evaluation using four target proteins (two kinases and two G protein-coupled receptors) showed that the generated molecules had a better binding affinity score (docking score) than the known active compounds, and the generated molecules possessed a broader chemical space distribution. SBMolGen not only generates novel binding active molecules but also presents 3D docking poses with target proteins, which will be useful in subsequent drug design. The code is available at https://github.com/clinfo/SBMolGen.

LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion.

The CLIP1-LTK fusion was recently discovered as a novel oncogenic driver in non-small cell lung cancer (NSCLC). Lorlatinib, a third-generation ALK inhibitor, exhibited a dramatic clinical response in a NSCLC patient harboring CLIP1-LTK fusion. However, it is expected that acquired resistance will inevitably develop, particularly by LTK mutations, as observed in NSCLC induced by oncogenic tyrosine kinases treated with corresponding tyrosine kinase inhibitors (TKIs). In this study, we evaluate eight LTK mutations corresponding to ALK mutations that lead to on-target resistance to lorlatinib. All LTK mutations show resistance to lorlatinib with the L650F mutation being the highest. In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.

Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer.

ALK gene rearrangement was observed in 3%-5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI-resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

Fibronectin type III domain-containing protein 5 interacts with APP and decreases amyloid ß production in Alzheimer's disease.

The deposition of Amyloid-beta peptides (Aß) is detected at an earlier stage in Alzheimer's disease (AD) pathology. Thus, the approach toward Aß metabolism is considered to play a critical role in the onset and progression of AD. Mounting evidence suggests that lifestyle-related diseases are closely associated with AD, and exercise is especially linked to the prevention and the delayed progression of AD. We previously showed that exercise is more effective than diet control against Aß pathology and cognitive deficit in AD mice fed a high-fat diet; however, the underlying molecular mechanisms remain poorly understood. On the other hand, a report suggested that exercise induced expression of fibronectin type III domain-containing protein 5 (FNDC5) in the hippocampus of mice through PGC1α pathway. Thus, in the current study, we investigated a possibility that FNDC5 interacts with amyloid precursor protein (APP) and affects Aß metabolism. As a result, for the first time ever, we found the interaction between FNDC5 and APP, and forced expression of FNDC5 significantly decreased levels of both Aß40 and Aß42 secreted in the media. Taken together, our results indicate that FNDC5 significantly affects ß-cleavage of APP via the interaction with APP, finally regulating Aß levels. A deeper understanding of the mechanisms by which the interaction between APP and FNDC5 may affect Aß production in an exercise-dependent manner would provide new preventive strategies against the development of AD.