Institut des Biomolécules Max Mousseron, CNRS, UMR 5247, Université de Montpellier, Faculté de Pharmacie, 15, Av. Charles Flahault, 34093 Montpellier, France.
CHU Grenoble Alpes, Université Grenoble Alpes, Grenoble, France.
Theranostics. 2020 Jan 12;10(5):2008-2028. doi: 10.7150/thno.40971. eCollection 2020.
CDK4/cyclin D kinase constitutes an attractive pharmacological target for development of anticancer therapeutics, in particular in -mutant lung cancer patients, who have a poor prognosis and no targeted therapy available yet. Although several ATP-competitive inhibitors of CDK4 have been developed for anticancer therapeutics, they suffer from limited specificity and efficacy. : As an alternative to ATP-competitive inhibitors we have designed a stapled peptide to target the main interface between CDK4 and cyclin D, and have characterized its physico-chemical properties and affinity to bind cyclin D1. : We have validated a positive correlation between CDK4/cyclin D level and mutation in lung cancer patients. The stapled peptide enters cells rapidly and efficiently, and inhibits CDK4 kinase activity and proliferation in lung cancer cells. Its intrapulmonary administration in mice enables its retention in orthotopic lung tumours and complete inhibition of their growth when co-administered with Abemaciclib. : The stapled peptide targeting the main interface between CDK4 and cyclin D provides promising therapeutic perspectives for patients with lung cancer.
CDK4/细胞周期蛋白 D 激酶构成了开发抗癌治疗药物的有吸引力的药理学靶点，特别是在 - 突变型肺癌患者中，这些患者预后不良，目前尚无靶向治疗药物。尽管已经开发了几种用于抗癌治疗的 ATP 竞争性 CDK4 抑制剂，但它们的特异性和疗效有限。 作为 ATP 竞争性抑制剂的替代物，我们设计了一种订书肽来靶向 CDK4 和细胞周期蛋白 D 之间的主要界面，并对其理化性质和与细胞周期蛋白 D1 结合的亲和力进行了表征。 我们已经验证了 CDK4/细胞周期蛋白 D 水平与肺癌患者中的 突变之间存在正相关关系。订书肽可快速有效地进入细胞，并抑制肺癌细胞中的 CDK4 激酶活性和增殖。在小鼠中进行肺内给药时，它可以保留在原位肺肿瘤中，并在与 Abemaciclib 共同给药时完全抑制其生长。 靶向 CDK4 和细胞周期蛋白 D 之间主要界面的订书肽为肺癌患者提供了有前途的治疗前景。
