c-KIT Small Molecule Inhibitors as a Therapeutic Strategy for Melanoma: Clinical Insights, SAR, and Future Directions

Arch Pharm (Weinheim). 2025 Oct;358(10):e70113. doi: 10.1002/ardp.70113.

Abstract

The proto-oncogene c-KIT plays a key role in several cellular processes such as cell growth, survival, and proliferation. The overexpression of c-KIT has been implicated with the pathogenesis of several malignancies, such as gastrointestinal stromal tumors, acute myeloid leukemia (AML), mastocytosis, and melanoma. Mutation of c-KIT has been observed in acral, mucosal, and chronically sun-damaged melanoma subtypes marking it as a key therapeutic target for melanoma. Moreover, the increasing incidence and mortality rate associated with melanoma further marks the importance of developing new therapeutic modalities. Herein, the progress in the design, structure-activity relationship, mechanisms, and development of c-KIT small molecule inhibitors for melanoma is discussed with the aim of guiding future c-KIT-based melanoma therapeutics.

Keywords: SAR; c‐KIT; melanoma; molecular docking; small molecule inhibitors.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Humans
  • Melanoma* / drug therapy
  • Melanoma* / metabolism
  • Melanoma* / pathology
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-kit* / antagonists & inhibitors
  • Proto-Oncogene Proteins c-kit* / genetics
  • Proto-Oncogene Proteins c-kit* / metabolism
  • Skin Neoplasms* / drug therapy
  • Skin Neoplasms* / pathology
  • Small Molecule Libraries* / chemistry
  • Small Molecule Libraries* / pharmacology
  • Structure-Activity Relationship

Substances

  • Proto-Oncogene Proteins c-kit
  • Antineoplastic Agents
  • Proto-Oncogene Mas
  • MAS1 protein, human
  • KIT protein, human
  • Protein Kinase Inhibitors
  • Small Molecule Libraries