Branched-chain amino acid transaminase 1 confers EGFR-TKI resistance through epigenetic glycolytic activation.

Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches.

ETU-Net: efficient Transformer and convolutional U-style connected attention segmentation network applied to endoscopic image of epistaxis.

Epistaxis is a typical presentation in the otolaryngology and emergency department. When compressive therapy fails, directive nasal cautery is necessary, which strongly recommended operating under the nasal endoscope if it is possible. Limited by the operator's clinical experience, complications such as recurrence, nasal ulcer, and septum perforation may occur due to insufficient or excessive cautery.

An Efficient Method for Monitoring Birds Based on Object Detection and Multi-Object Tracking Networks.

To protect birds, it is crucial to identify their species and determine their population across different regions. However, currently, bird monitoring methods mainly rely on manual techniques, such as point counts conducted by researchers and ornithologists in the field. This method can sometimes be inefficient, prone to errors, and have limitations, which may not always be conducive to bird conservation efforts.

Design, synthesis and biological evaluation of KRAS-PROTACs.

Several small-molecule covalent inhibitors of KRAS have made breakthrough progress in the treatment of KRAS mutant cancer. However, the clinical application of KRAS small-molecule inhibitors may be limited by adaptive resistance. Emerging PROTAC strategy can achieve complementary advantages with small molecule inhibitors and improve anti-tumor efficacy.

Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation and .

Osimertinib (AZD9291), a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), has significantly improved the survival of non-small cell lung cancer (NSCLC) patients with EGFR mutation, the major mechanism of acquired resistance to first-generation EGFR TKI. However, resistance to AZD9291 arises eventually and EGFR mutation was reported to be a major resistance mechanism. Thus, it is highly valuable to develop novel EGFR fourth-generation inhibitors targeting C797S mutation to override the acquired resistance.

ASK120067 potently suppresses B-cell or T-cell malignancies and by inhibiting BTK and ITK.

Hyperactivation of Bruton's tyrosine kinase (BTK) or interleukin-2-inducible T cell kinase (ITK) has been attributed to the pathogenesis of B-cell lymphoma or T-cell leukemia, respectively, which suggests that Bruton's tyrosine kinase and interleukin-2-inducible T cell kinase are critical targets for the treatment of hematological malignancies. We identified a novel third-generation epidermal growth factor receptor (EGFR) inhibitor, ASK120067 (limertinib) in our previous research, which has been applied as a new drug application against non-small cell lung cancer in China. In this work, we found that ASK120067 displayed potent inhibitory efficacy against Bruton's tyrosine kinase protein and interleukin-2-inducible T cell kinase protein covalent binding.

Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations.

Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5'-triphosphate-competitive or allosteric EGFR inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFR inhibitors by using a macrocyclization strategy.

Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR Mutants.

A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFR inhibitors. One of the most potent and selective compounds strongly suppressed the EGFR and EGFR kinases with IC values of 0.7 and 3.

LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo.

With the wide clinical use of the third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC), acquired resistance caused by EGFR C797S tertiary mutation has become a concern. Therefore, fourth-generation EGFR inhibitors that could overcome this mutation have gained increasing attention in recent years. Here, we identified LS-106 as a novel EGFR inhibitor against C797S mutation and evaluated its antitumor activity both in vitro and in vivo.

Design, synthesis and pharmacological evaluation of bicyclic and tetracyclic pyridopyrimidinone analogues as new KRAS inhibitors.

KRAS is the most commonly altered oncogene of the RAS family, especially the G12C mutant (KRAS), which has been a promising drug target for many cancers. On the basis of the bicyclic pyridopyrimidinone framework of the first-in-class clinical KRAS inhibitor AMG510, a scaffold hopping strategy was conducted including a F-OH cyclization approach and a pyridinyl N-atom working approach leading to new tetracyclic and bicyclic analogues. Compound 26a was identified possessing binding potency of 1.

Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation.

The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site.

Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance.

Background: Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors; however, the efficacy of these drugs is limited by acquired resistance driven by the EGFR mutation. The discovery of third-generation EGFR inhibitors overcoming EGFR and their new resistance mechanisms have attracted much attention.

Methods: We examined the antitumor activities and potential resistance mechanism of a novel EGFR third-generation inhibitor in vitro and in vivo using ELISA, SRB assay, immunoblotting, flow cytometric analysis, kinase array, qRT-PCR and tumor xenograft models.

Discovery and biological evaluation of N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-2-oxo-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide as potent Bruton's tyrosine kinase inhibitors.

Bruton's tyrosine kinase (BTK) is a key component of the B cell receptor (BCR) signaling pathway and plays a crucial role in B cell malignancies and autoimmune disorders; thus, it is an attractive target for the treatment of B cell related diseases. Here, we evaluated the BTK inhibitory activity of a series of pyrimido[4,5-d][1,3]oxazin-2-one derivatives. Combining this evaluation with structure-activity relationship (SAR) analysis, we found that compound 2 exhibited potent BTK kinase inhibitory activity, with an IC of 7 nM.

Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR).

Tertiary EGFR mutation induced resistance against osimertinib () is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFR inhibitors. A representative compound, , exhibited an IC of 27.

Discovery and Biological evaluation of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors.

Aberrant activation of B cell receptor (BCR) signal transduction cascade contributes to the propagation and maintenance of B cell malignancies. The discovery of mall molecules with high potency and selectivity against Bruton's tyrosine kinase (BTK), a key signaling molecule in this cascade, is particularly urgent in modern treatment regimens. Herein, a series of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives were reported as potent BTK inhibitors.