Inhibition of Nutlin-Resistant HDM2 Mutants by Stapled Peptides

Pharmacological modulation of p53 activity is an attractive therapeutic strategy in cancers with wild-type p53. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2, a key negative regulator of p53 and blocks its activity. We have described resistance mutations in HDM2 that selectively reduce affinity for Nutlin but not p53. In the present communication, we show that stapled peptides targeting the same region of HDM2 as Nutlin are refractory to these mutations, and display reduced discrimination between the wild-type and mutant HDM2s with regards to functional abrogation of interaction with p53. The larger interaction footprint afforded by stapled peptides suggests that this class of ligands may prove comparatively more resilient to acquired resistance in a clinical setting.对p53活性实施药理学调控，是野生型p53阳性肿瘤极具潜力的治疗策略。目前处于临床试验阶段的小分子Nutlin-3A，可竞争性结合作为p53关键负调控因子的人类双微体2（HDM2），并阻断其活性。我们此前已报道HDM2中存在一类耐药突变，该类突变可选择性降低HDM2与Nutlin的结合亲和力，却不影响其与p53的相互作用。在本研究通讯中，我们证实，与Nutlin靶向HDM2同一区域的钉肽（stapled peptides），不受上述耐药突变的影响；且在阻断与p53相互作用的功能层面，这类肽对野生型与突变型HDM2的识别选择性有所降低。钉肽所具备的更大结合界面提示，这类配体在临床场景中，对获得性耐药具备更强的抵御能力。