Advances of dual inhibitors based on ALK for the treatment of cancer.

in Bioorganic chemistry by Jin-Feng Chen, Shu-Jin Guo, Bin He, Wei Zheng, Wen-Jie Jiang, Zhuo Yuan, Yu Xiang, Cheng Peng, Wei Xiong, Jian-You Shi

TLDR

  • ALK dual inhibitors offer improved treatment efficacy and reduced emergence of drug resistance compared to single-target inhibitors in ALK-mutant NSCLC.

Abstract

Anaplastic lymphoma kinase (ALK), which encodes a highly conserved receptor tyrosine kinase (RTK), is important for the development and progression of many tumors, especially non-small cell lung cancer (NSCLC). Currently, third-generation ALK inhibitors are used to treat ALK-mutant NSCLC, but the rapid emergence of resistance during treatment greatly limits their efficacy in clinic. In comparison to single-target inhibitors, ALK dual inhibitors offer the benefits of reducing the emergence of drug resistance, improving treatment efficacy, and optimizing pharmacokinetic features due to the synergistic function of ALK and other associated targets involved in tumor progression. Therefore, we outline the development of ALK dual inhibitors, highlight their design approaches and structure-activity relationship (SAR), and offer insights into new challenges and potential future directions in this area.

Overview

  • The study focuses on the development of ALK dual inhibitors to improve treatment efficacy and reduce the emergence of drug resistance in ALK-mutant NSCLC.
  • The study aims to outline the design approaches and structure-activity relationship (SAR) of ALK dual inhibitors.
  • The primary objective is to identify potential future directions in the development of ALK dual inhibitors to address the limitations of current treatment.

Comparative Analysis & Findings

  • ALK dual inhibitors offer a synergistic function of ALK and other associated targets, which reduces the emergence of drug resistance and improves treatment efficacy.
  • The design approaches and SAR of ALK dual inhibitors will provide insights into the optimization of pharmacokinetic features and the improvement of treatment efficacy.
  • The study highlights the benefits of ALK dual inhibitors over single-target inhibitors, including reducing the emergence of drug resistance, improving treatment efficacy, and optimizing pharmacokinetic features.

Implications and Future Directions

  • The development of ALK dual inhibitors offers potential solutions to overcome the limitations of current treatment in clinic.
  • New challenges and potential future directions in the development of ALK dual inhibitors include addressing the emergence of resistance, optimizing pharmacokinetic features, and identifying optimal combination regimens.
  • The insights gained from this study will inform the design of new ALK dual inhibitors and guide future research in this area.
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