MIRA: Atropisomerism as a means to increase target selectivity and as inspiration for new chemistry

我们的研究计划的主要目标是利用阻转异构作为设计原则，以增加 混杂的生物活性小分子的选择性。阻转异构是一种手性形式， 从键周围的差异取代，其中旋转构象是对映异构体。阻转异构现象 与传统的“点”手性的不同之处在于外消旋化可以通过键旋转发生，因此取决于 阻转异构体可以作为稳定的可分离的对映异构体存在，或者 互变阻转异构体混合物。许多具有生物活性的小分子以快速相互转化的形式存在， 阻转异构体，但与其他阻转异构体以阻转异构体特异性方式结合其生物靶标 对所需活动贡献不大。这使我们假设， 锁定在单一阻转异构体中的混杂生物活性化合物将具有增加的靶向 由于排除了由其他阻转异构体引起的脱靶效应，因此具有选择性。 为了支持这一假设，我们已经获得了阻转异构体纯类似物的初步结果， 的混杂激酶抑制剂（KI）具有改善的激酶选择性。这是有影响力的，因为 激酶是肿瘤学中最重要的药物靶标之一，然而， 已经使得大多数KI没有选择性。这种滥交可能导致患者的副作用。 这些问题以RET激酶为例，RET激酶是许多癌症的有效治疗靶点， 存在选择性抑制剂。在本申请的第一部分中，我们提出优化铅的结构， “阻转异构体预组织”（AP）对RET的效力和选择性KI。这些活动的预期成果 研究将是一组选择性RET抑制剂，作为副作用较少的癌症治疗方法的先导 作为有价值的化学探针，可以用来更好地了解RET在这些癌症中的作用。移动 此外，我们还提出了AP在其他靶激酶和混杂蛋白类中的更广泛应用。 抑制剂如β-螺旋模拟物。 阻转异构体纯类似物的获得目前是该领域的主要瓶颈。虽然准备 “手性HPLC”可为初始研究提供对映体纯的类似物，材料的通量相对适中 效率低下。因此，我们研究计划的第二个长期目标是开发新的 允许将不同的取代并入不同的 阻转异构体的类别。为了支持这一点，我们有几个新的反应的初步结果，允许 在阻转异构体轴附近引入几个不同的基团。在这个MIRA中，我们寻求 优化这些反应并将这些反应性扩展到挑战药物相关阻转异构体 脚手架这些研究的预期成果将是一流的路线，以几个类， 阻转异构体，这将加快阻转异构体构象在药物发现中的作用的研究。

The major goal of our research program is to exploit atropisomerism as a design principle to increase the selectivity of promiscuous biologically active small molecules. Atropisomerism is a form of chirality that arises from differential substitution around a bond where the rotational conformers are enantiomers. Atropisomerism differs from traditional `point' chirality in that racemization can occur via bond rotation, and thus depending on the degree of hindrance to rotation around this bond, atropisomers can exist as stable isolable enantiomers or interconverting atropisomeric mixtures. Many biologically active small molecules exist as rapidly interconverting atropisomers, yet bind to their biological targets in an atropisomer-specific manner, with the other atropisomer contributing little to the desired activities. This has led us to hypothesize that the design of analogs of promiscuous biologically active compounds that are locked into a single atropisomer will have increased target selectivity due to preclusion of off-target effects caused by the other atropisomer. In support of this hypothesis we have obtained preliminary results in which atropisomerically pure analogs of promiscuous kinase inhibitors (KIs) possessed improved kinase selectivity. This is impactful because kinases are one of the most important drug targets in oncology, however a significant amount of conservation throughout the kinome has rendered most KIs unselective. This promiscuity can lead to side effects in patients. These issues are exemplified by RET kinase, a validated therapeutic target for numerous cancers for which no selective inhibitor exists. In the first part of this application we propose to optimize the structure of lead `atropisomer preorganized' (AP) KIs for potency and selectivity towards RET. The expected outcome of these studies will be a set of selective RET inhibitors as leads towards cancer therapeutics with fewer side effects and as valuable chemical probes that can be used to better understand RET's roles in these cancers. Moving forward we also propose a broader application of AP to other target kinases and classes of promiscuous inhibitor such as mimetics of -helices. Access to atropisomerically pure analogs is currently a major bottleneck in the field. While preparative `chiral HPLC' can provide enantiopure analogs for initial studies, the throughput of material is relatively modest and inefficient. Because of this, a second long-term goal of our research program is the development of new catalytic atroposelective methodologies that allow for the incorporation of diverse substitutions into diverse classes of atropisomer. In support of this we have preliminary results for several novel reactions that allow for the incorporation of several different groups adjacent to an atropisomeric axis. In this MIRA we seek to optimize these reactions and extend these reactivities to challenging pharmaceutically relevant atropisomeric scaffolds. The expected outcomes of these studies will be first-in-class routes towards several classes of atropisomer that will expedite the study of the effects of atropisomer conformation in drug discovery.