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<p>Malignant melanoma, a heterogeneous neoplasm arising from melanocytes, is driven by mutations in critical signaling pathways, including MAPK and PI3K-AKT. Despite the improvement in patient outcomes achieved through targeted therapies such as BRAF inhibitors, the persistence of drug resistance poses a significant challenge. This underscores the necessity for the development of novel small molecule therapeutics and combination treatment strategies. Currently, several strategies show promise in addressing drug resistance, including the targeting of RAF dimers, modulation of MAPK pathway components such as SOS1/SHP2 and ERK, regulation of cyclins, and the integration of these approaches with immunotherapy. This review highlights recent advancements in small molecule therapeutics for melanoma, focusing on those targeting key pathogenic proteins and their combination strategies. It also explores future directions in precision medicine based on molecular profiling and drug resistance mechanisms, aiming to provide a theoretical foundation for research and clinical applications.</p><p></p>

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Small-molecule drug discovery in malignant melanoma: current status and prospective developments

  • 期刊论文

  • 发表日期：

    2025年12月21日

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  • Xiaohui Miao,
  • Yangyang Liu,
  • Chunxin Li,
  • Junlong Wu,
  • Ying Li,
  • Zhihan Li,
  • Jingjing Li,
  • Ying Sun,
  • Jicheng Han

摘要

Malignant melanoma, a heterogeneous neoplasm arising from melanocytes, is driven by mutations in critical signaling pathways, including MAPK and PI3K-AKT. Despite the improvement in patient outcomes achieved through targeted therapies such as BRAF inhibitors, the persistence of drug resistance poses a significant challenge. This underscores the necessity for the development of novel small molecule therapeutics and combination treatment strategies. Currently, several strategies show promise in addressing drug resistance, including the targeting of RAF dimers, modulation of MAPK pathway components such as SOS1/SHP2 and ERK, regulation of cyclins, and the integration of these approaches with immunotherapy. This review highlights recent advancements in small molecule therapeutics for melanoma, focusing on those targeting key pathogenic proteins and their combination strategies. It also explores future directions in precision medicine based on molecular profiling and drug resistance mechanisms, aiming to provide a theoretical foundation for research and clinical applications.