Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, Maryland, USA.
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Med Res Rev. 2022 Mar;42(2):770-799. doi: 10.1002/med.21863. Epub 2021 Oct 25.
Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same-allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure-based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor-specific network, ushering innovative considerations in precision medicine.
精准肿瘤学受益于有效的早期药物发现决策。最近，针对无活性蛋白构象的药物研发取得了令人瞩目的成功，这引发了一些基本问题，即哪些靶点可以从中受益，以及活性/无活性蛋白药理学的原理是什么。致癌驱动突变已被确定可模拟蛋白激活机制。我们认为，是否针对无活性（或活性）构象进行靶向治疗的决策应主要取决于蛋白的激活机制。接下来，我们将讨论最近鉴定的双（多）相同等位基因驱动突变及其对细胞增殖的影响，并提出与单驱动突变类似，双驱动突变也模拟了激活机制。我们还提出，双（多）顺式突变的结构扰动可能会揭示新的药物设计表面/口袋。最后，我们强调了细胞网络在癌症中失调的首要作用。我们基于结构的综述和展望更新了传统的作用机制，为决策提供了信息，并提请注意靶蛋白的固有激活机制和重新布线的肿瘤特异性网络，为精准医学带来了创新性的考虑。
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