Resistance phenomena, especially acquired drug resistance, have been severely hampering the application of chemotherapeutics during cancer chemotherapy. Autophagy plays a role in maintaining the survival of cancer cells and might mediate resistance to chemotherapy drugs. Herein, a new series of 5‐amino‐2‐ether‐benzamide derivatives were synthesized and evaluated as autophagy inhibitors. Selected from 14 synthesized compounds as lead autophagy inhibitor, N‐(cyclohexylmethyl)‐5‐(((cyclohexylmethyl)amino)methyl)‐2‐((4‐(trifluoromethyl)benzyl)oxy)benzamide (4 d) showed the most obvious effect of LC3B protein conversion. Further, its autophagy inhibition, evaluated by using transmission electron microscopy and confocal microscopy, showed that the fusion of autophagosomes and lysosomes in the final stage of autophagic flux was suppressed. We also found that 4 d could enhance the chemosensitivity of vincristine in vincristine‐resistant esophageal cancer cell line Eca109/VCR in a synergistic, associative manner. Moreover, a computational study showed that 4 d might bind with p62‐zz to inhibit autophagy. We also found 4 d to be relatively less cytotoxic to normal cells versus cancer cells than the reported p62‐zz inhibitor.
In recent years, the flourishing of synthetic methodology studies has provided concise access to numerous molecules with new chemical space. These compounds form a large library with unique scaffolds, but their application in hit discovery is not systematically evaluated. In this work, we establish a synthetic methodology-based compound library (SMBL), integrated with compounds obtained from our synthetic researches, as well as their virtual derivatives in significantly larger scale. We screen the library and identify small-molecule inhibitors to interrupt the protein–protein interaction (PPI) of GIT1/β-Pix complex, an unrevealed target involved in gastric cancer metastasis. The inhibitor 14-5-18 with a spiro[bicyclo[2.2.1]heptane-2,3’-indolin]−2’-one scaffold, considerably retards gastric cancer metastasis in vitro and in vivo. Since the PPI targets are considered undruggable as they are hard to target, the successful application illustrates the structural specificity of SMBL, demonstrating its potential to be utilized as compound source for more challenging targets.
The rapid and efficient hit discovery is highly dependent on the development of multifarious chemical libraries. In recent years, the flourishing of synthetic methodology studies has provided concise access to numerous molecules with new chemical space. These compounds form a large library with unique scaffolds, but their application in hit compounds screening has not been systematically evaluated. In the present work, we have established a synthetic methodology-based compound library (SMBL), integrated of compounds obtained from our synthetic researches, as well as their virtual derivatives in significantly larger scale. We further screened the library and identified the first small-molecule inhibitors to interrupt the protein–protein interaction (PPI) of GIT1/β-Pix complex, an unrevealed target involved in gastric cancer metastasis. The inhibitor 14-5-18 with a spiro[bicyclo[2.2.1]heptane-2,3'-indolin]-2'-one scaffold, considerably retarded gastric cancer metastasis in vitro and in vivo. Since the PPI targets are considered “undruggable” that were hard to be targeted, the successful identification of the inhibitor illustrated the structural diversity and specificity of SMBL, demonstrating its potential to be utilized as compound source for targeting some challenging targets.
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