In the search of biguanide-derived molecules against melanoma, we have discovered and developed a series of bioactive products and identified the promising new compound CRO15. This molecule exerted anti-melanoma effects on cells lines and cells isolated from patients including the ones derived from tumors resistant to BRAF inhibitors. Moreover, CRO15 was able to decrease viability of cells lines from a broad range of cancer types. This compound acts by two distinct mechanisms. First by activating the AMPK pathway induced by a mitochondrial disorder. Second by inhibition of MELK kinase activity, which induces cell cycle arrest and activation of DNA damage repair pathways by p53 and REDD1 activation. All of these mechanisms activate autophagic and apoptotic processes resulting in melanoma cell death. The strong efficacy of CRO15 to reduce the growth of melanoma xenograft sensitive or resistant to BRAF inhibitors opens interesting perspective.

在寻找抗黑色素瘤的双胍衍生分子的过程中，我们发现并开发了一系列生物活性产品，并确定了有前景的新化合物CRO15。该分子对从患者身上分离的细胞系和细胞发挥抗黑色素瘤作用，包括源自对 BRAF 抑制剂具有抗性的肿瘤的细胞。此外，CRO15 能够降低来自多种癌症类型的细胞系的活力。这种化合物通过两种不同的机制起作用。首先通过激活线粒体疾病诱导的 AMPK 通路。其次是通过抑制 MELK 激酶活性，通过 p53 和 REDD1 激活诱导细胞周期停滞和 DNA 损伤修复途径的激活。所有这些机制都会激活自噬和凋亡过程，导致黑色素瘤细胞死亡。