BCI-215, a Dual-Specificity Phosphatase Inhibitor, Reduces UVB-Induced Pigmentation in Human Skin by Activating Mitogen-Activated Protein Kinase Pathways

  • Molecules. 2022 Aug 25;27(17):5449. doi: 10.3390/molecules27175449.
Jeong Hyeon Lee  1  2 ,  Myoung Eun Choi  2 ,  Hongchan An  3 ,  Ju Won Moon  1  2 ,  Hye Jin Yeo  1  4 ,  Youngsup Song  4 ,  Sung Eun Chang  2
Affiliations
  • 1. Department of Biomedical Sciences, Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Ulsan 44610, Korea.
  • 2. Department of Dermatology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
  • 3. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea.
  • 4. Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea.
PMID: 36080217 DOI: 10.3390/molecules27175449
Abstract

Background: The dysregulation of melanin production causes skin-disfiguring ultraviolet (UV)-associated hyperpigmented spots. Previously, we found that the activation of c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase (MAPK), inhibited melanogenesis.

Methods: We selected BCI-215 as it may modify MAPK expression via a known function of a dual-specificity Phosphatase (DUSP) 1/6 inhibitor. B16F10 melanoma cells, Mel-ab cells, human melanocytes, and a coculture were used to assess the anti-melanogenic activity of BCI-215. The molecular mechanisms were deciphered by assaying the melanin content and cellular Tyrosinase activity via immunoblotting and RT-PCR.

Results: BCI-215 was found to suppress basal and cAMP-stimulated melanin production and cellular Tyrosinase activity in vitro through the downregulation of microphthalmia-associated transcription factor (MITF) protein and its downstream Enzymes. The reduction in MITF expression caused by BCI-215 was found to be due to all three types of MAPK activation, including extracellular signal-regulated kinase (ERK), JNK, and p38. The degree of activation was greater in ERK. A phosphorylation of the β-catenin pathway was also demonstrated. The melanin index, expression of MITF, and downstream Enzymes were well-reduced in UVB-irradiated ex vivo human skin by BCI-215.

Conclusions: As BCI-215 potently inhibits UV-stimulated melanogenesis, small molecules of DUSP-related signaling modulators may provide therapeutic benefits against pigmentation disorders.

Keywords
BCI-215; dual-specificity phosphatase; melanogenesis; mitogen-activated protein kinase; ultraviolet radiation.
Products