Research strategies of small molecules as chemotherapeutics to overcome multiple myeloma resistance.

Multiple myeloma (MM), a cancer of plasma cells, is the second most common hematological malignancy which is characterized by aberrant plasma cells infiltration in the bone marrow and complex heterogeneous cytogenetic abnormalities. Over the past two decades, novel treatment strategies such as proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved the relative survival rate of MM patients. However, the development of drug resistance results in the majority of MM patients suffering from relapse, limited treatment options and uncontrolled disease progression after relapse. There are urgent needs to develop and explore novel MM treatment strategies to overcome drug resistance and improve efficacy. Here, we review the recent small molecule therapeutic strategies for MM, and introduce potential new targets and corresponding modulators in detail. In addition, this paper also summarizes the progress of multi-target inhibitor therapy and protein degradation technology in the treatment of MM.

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations.

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 µΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 µM and 0.64 µM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.

Preclinical characterization of danatinib as a novel FLT3 inhibitor with excellent efficacy against resistant acute myeloid leukemia.

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.

Brain-Machine Coupled Learning Method for Facial Emotion Recognition.

Neural network models of machine learning have shown promising prospects for visual tasks, such as facial emotion recognition (FER). However, the generalization of the model trained from a dataset with a few samples is limited. Unlike the machine, the human brain can effectively realize the required information from a few samples to complete the visual tasks. To learn the generalization ability of the brain, in this article, we propose a novel brain-machine coupled learning method for facial emotion recognition to let the neural network learn the visual knowledge of the machine and cognitive knowledge of the brain simultaneously. The proposed method utilizes visual images and electroencephalogram (EEG) signals to couple training the models in the visual and cognitive domains. Each domain model consists of two types of interactive channels, common and private. Since the EEG signals can reflect brain activity, the cognitive process of the brain is decoded by a model following reverse engineering. Decoding the EEG signals induced by the facial emotion images, the common channel in the visual domain can approach the cognitive process in the cognitive domain. Moreover, the knowledge specific to each domain is found in each private channel using an adversarial strategy. After learning, without the participation of the EEG signals, only the concatenation of both channels in the visual domain is used to classify facial emotion images based on the visual knowledge of the machine and the cognitive knowledge learned from the brain. Experiments demonstrate that the proposed method can produce excellent performance on several public datasets. Further experiments show that the proposed method trained from the EEG signals has good generalization ability on new datasets and can be applied to other network models, illustrating the potential for practical applications.

Discovery of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine derivatives as novel FLT3 covalent inhibitors for the intervention of acute myeloid leukemia.

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 µM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML.

Design and synthesis of selective FLT3 inhibitors via exploration of back pocket II.

Aim: The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity and potency is of necessity. Methods & results: The authors used computational methods to systematically compare pocket similarity with 269 kinases. Subsequently, based on these investigations and beginning with in-house compound 10, they synthesized a series of 6-methyl-isoxazol[3,4-b]pyridine-3-amino derivatives and identified that compound 45 (IC50: 103 nM) displayed gratifying potency in human AML cell lines with FLT3-internal tandem duplications mutation as well as FLT3-internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells. Conclusion: The integrated biological activity results indicated that compound 45 deserves further development for therapeutic remedies for AML.

LiDAR Intensity Completion: Fully Exploiting the Message from LiDAR Sensors.

Light Detection and Ranging (LiDAR) systems are novel sensors that provide robust distance and reflection strength by active pulsed laser beams. They have significant advantages over visual cameras by providing active depth and intensity measurements that are robust to ambient illumination. However, the systemsstill pay limited attention to intensity measurements since the output intensity maps of LiDAR sensors are different from conventional cameras and are too sparse. In this work, we propose exploiting the information from both intensity and depth measurements simultaneously to complete the LiDAR intensity maps. With the completed intensity maps, mature computer vision techniques can work well on the LiDAR data without any specific adjustment. We propose an end-to-end convolutional neural network named LiDAR-Net to jointly complete the sparse intensity and depth measurements by exploiting their correlations. For network training, an intensity fusion method is proposed to generate the ground truth. Experiment results indicate that intensity-depth fusion can benefit the task and improve performance. We further apply an off-the-shelf object (lane) segmentation algorithm to the completed intensity maps, which delivers consistent robust to ambient illumination performance. We believe that the intensity completion method allows LiDAR sensors to cope with a broader range of practice applications.

Synthesis and biological evaluation of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine covalent inhibitors as potential agents for the treatment of acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC50 = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 µM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC50 > 10 µM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.

RGB-D SLAM in Dynamic Environments Using Point Correlations.

In this paper, a simultaneous localization and mapping (SLAM) method that eliminates the influence of moving objects in dynamic environments is proposed. This method utilizes the correlation between map points to separate points that are part of the static scene and points that are part of different moving objects into different groups. A sparse graph is first created using Delaunay triangulation from all map points. In this graph, the vertices represent map points, and each edge represents the correlation between adjacent points. If the relative position between two points remains consistent over time, there is correlation between them, and they are considered to be moving together rigidly. If not, they are considered to have no correlation and to be in separate groups. After the edges between the uncorrelated points are removed during point-correlation optimization, the remaining graph separates the map points of the moving objects from the map points of the static scene. The largest group is assumed to be the group of reliable static map points. Finally, motion estimation is performed using only these points. The proposed method was implemented for RGB-D sensors, evaluated with a public RGB-D benchmark, and tested in several additional challenging environments. The experimental results demonstrate that robust and accurate performance can be achieved by the proposed SLAM method in both slightly and highly dynamic environments. Compared with other state-of-the-art methods, the proposed method can provide competitive accuracy with good real-time performance.

Development of Taccalonolide AJ-Hydroxypropyl-ß-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma.

BACKGROUND: Microtubule-targeted drugs are the most effective drugs for adult patients with certain solid tumors. Taccalonolide AJ (AJ) can stabilize tubulin polymerization by covalently binding to ß-tubulin, which enables it to play a role in the treatment of tumors. However, its clinical applications are largely limited by low water solubility, chemical instability in water, and a narrow therapeutic window. Clear-cell renal-cell carcinoma (cc RCC) accounts for approximately 70% of RCC cases and is prone to resistance to particularly targeted therapy drugs. METHODS: we prepared a water-soluble cyclodextrin-based carrier to serve as an effective treatment for cc RCC. RESULTS: Compared with AJ, taccalonolide AJ-hydroxypropyl-ß-cyclodextrin (AJ-HP-ß-CD) exhibited superior selectivity and activity toward the cc RCC cell line 786-O vs. normal kidney cells by inducing apoptosis and cell cycle arrest and inhibiting migration and invasion of tumor cells in vitro. According to acute toxicity testing, the maximum tolerated dose (MTD) of AJ-HP-ß-CD was 10.71 mg/kg, which was 20 times greater than that of AJ. Assessment of weight changes showed that mouse body weight recovered over 7-8 days, and the toxicity could be greatly reduced by adjusting the injections from once every three days to once per week. In addition, we inoculated 786-O cells to generate xenografted mice to evaluate the anti-tumor activity of AJ-HP-ß-CD in vivo and found that AJ-HP-ß-CD had a better tumor inhibitory effect than that of docetaxel and sunitinib in terms of tumor growth and endpoint tumor weight. These results indicated that cyclodextrin inclusion greatly increased the anti-tumor therapeutic window of AJ. CONCLUSIONS: the AJ-HP-ß-CD complex developed in this study may prove to be a novel tubulin stabilizer for the treatment of cc RCC. In addition, this drug delivery system may broaden the horizon in the translational study of other chemotherapeutic drugs.

One-pot synthesis of indoles and quinolinones from ortho-tosylaminophenyl-substituted para-quinone methides.

A facile one-pot synthesis has been developed through alkylation/acylation of ortho-tosylaminophenyl-substituted para-quinone methides followed by an intramolecular 1,6-conjugate addition and oxidation sequence. This cascade reaction occurs readily in good yield (up to 95%), providing a divergent synthetic approach to structurally diverse 2,3-disubstituted indoles and 3,4-diaryl-substituted quinolinones.

Development of Orally Active Thrombin Inhibitors for the Treatment of Thrombotic Disorder Diseases.

Thrombotic disorders represent the major share of the various cardiovascular diseases, and significant progress has been made in the development of synthetic thrombin inhibitors as new anticoagulants. In addition to the development of highly potent and selective inhibitors with improved safety and suitable half-life, several allosteric inhibitors have been designed and synthesized, that did not fully nullify the procoagulant signal and thus could result in reduced bleeding complications. Furthermore, natural products with thrombin inhibitory activity have been isolated, and some natural products have been modified in order to improve their inhibitory activity and metabolic stability. This review summarizes the development of orally active thrombin inhibitors for the treatment of thrombotic disorder diseases, which could serve as a reference for the interested researchers.