MYC is a key transcriptional regulator involved in cellular proliferation and has established roles in transcriptional elongation and initiation, microRNA regulation, apoptosis, and pluripotency. Despite this prevalence, functional chemical probes of MYC function at the protein level have been limited. Previously, we discovered 5a, that binds to MYC with potency and specificity, downregulates the transcriptional activities of MYC and shows efficacy in vivo. However, this scaffold posed intrinsic pharmacokinetic liabilities, namely, poor solubility that precluded biophysical interrogation. Here, we developed a screening platform based on field-effect transistor analysis (Bio-FET), surface plasmon resonance (SPR), and a microtumor formation assay to analyze a series of new compounds aimed at improving these properties. This blind SAR campaign has produced a new lead compound of significantly increased in vivo stability and solubility for a 40-fold increase in exposure. This probe represents a significant advancement that will not only enable biophysical characterization of this interaction and further SAR, but also contribute to advances in understanding of MYC biology.

MYC是参与细胞增殖的关键转录调节因子，并在转录延伸和起始，microRNA调节，凋亡和多能性方面发挥了重要作用。尽管有这种流行，但是在蛋白质水平上MYC功能的功能性化学探针仍受到限制。以前，我们发现5a能够有效和特异性地结合MYC，下调MYC的转录活性并在体内显示出功效。但是，该支架具有固有的药代动力学特性，即溶解性差，因而无法进行生物物理询问。在这里，我们开发了一种基于场效应晶体管分析（Bio-FET），表面等离子体共振（SPR）和微肿瘤形成分析的筛选平台，以分析旨在改善这些特性的一系列新化合物。这种盲目的SAR运动产生了一种新的先导化合物，其体内稳定性和溶解度显着提高，暴露量增加40倍。该探针代表了一项重大进展，不仅将使这种相互作用和进一步的SAR的生物物理表征，而且有助于了解MYC生物学的进展。