Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin‐2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B‐Raf and MEK inhibitors and allow the treatment of patients with B‐Raf mutated melanoma. Second, there are the immunotherapies, with anti‐CTLA‐4 and anti‐PD‐1 antibodies that are used for patients harboring a B‐Raf wild‐type status. Both approaches have significantly improved patient survival, compared with alkylating agents, in the treatment of unresectable melanoma. Herein, we review the evolution of the treatment of melanoma starting from early discoveries to current therapies. A focus will be provided on drug discovery, synthesis, and mode of action of relevant drugs and the future directions of the domain to overcome the emergence of the resistance events.

中文翻译：

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转移性黑素瘤：治疗方法的发展和未来挑战的见解

黑色素瘤是皮肤癌最致命的形式。虽然早期诊断出的相关生存预后良好，但是当黑色素瘤发展成转移形式时，其生存率会急剧下降。在2011年之前，无论其效率低下还是毒性低下，最受欢迎的疗法包括白介素-2和化学疗法。根据重要的生物学发现，已经批准了两种新型治疗方法。首先，有针对性的疗法，它依赖于小分子B‐Raf和MEK抑制剂，可以治疗B‐Raf突变的黑色素瘤患者。其次，存在具有抗CTLA-4和抗PD-1抗体的免疫疗法，用于具有B-Raf野生型状态的患者。与烷基化剂相比，这两种方法在不可切除的黑色素瘤治疗中均显着提高了患者的生存率。在此处，我们回顾了从早期发现到当前疗法的黑素瘤治疗方法的发展。将重点介绍相关药物的药物发现，合成和作用方式，以及克服耐药性事件出现的领域的未来方向。