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

我们研究计划的主要目标是利用反常异构性作为设计原则，以增加 混杂生物活性小分子的选择性。异构性是手性的一种形式 从一个键周围的差异取代，其中旋转构象是对映体。反常异构症 与传统的‘点’手性不同的是，外消旋可以通过键的旋转发生，因此依赖于 围绕这个键旋转的阻碍程度，阿托品可以作为稳定的、可分离的对映体或 相互转化阿托品混合物。许多生物活性小分子以快速相互转化的方式存在 阿托品，但与另一种阿托品以阿托品特异性的方式与其生物靶标结合 对想要的活动贡献很少。这让我们假设，类似的设计 锁定在单一阿托品中的混杂生物活性化合物将增加靶标。 由于排除了另一种阿托品引起的脱靶效应而产生的选择性。 为了支持这一假设，我们已经获得了初步的结果，在这些结果中，反常异构性的纯类似物 混杂蛋白激酶抑制剂(KIS)具有更高的蛋白激酶选择性。这是有影响力的，因为 激酶是肿瘤学中最重要的药物靶点之一，然而有相当大的保守量 在整个显性基因组中，大多数KI都是没有选择性的。这种乱交可能会导致患者的副作用。 RET激酶就是这些问题的例证，它是许多癌症的有效治疗靶点，对这些癌症没有 存在选择性抑制剂。在本应用程序的第一部分中，我们建议优化Lead的结构 ‘阿托品预组化体’(AP)KIS，用于RET的效力和选择性。这些措施的预期结果是什么 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。搬家 此外，我们还建议将AP更广泛地应用于其他靶向激酶和混杂类别 抑制剂，如-螺旋的模拟。 目前，获得异构体纯类似物是该领域的一个主要瓶颈。在准备过程中 手性高效液相色谱法可以为初步研究提供对映体类似物，材料的吞吐量相对较小。 而且效率低下。正因为如此，我们研究计划的第二个长期目标是开发新的 催化阿托品选择性方法，允许将不同的取代基结合到不同的 阿托品的分类。为了支持这一点，我们有几个新反应的初步结果，这些反应允许 不同基团的结合在一个异向体轴附近的几个不同的基团的结合在这部米拉中，我们试图 优化这些反应，并将这些反应扩展到挑战药物相关的阿托品 脚手架。这些研究的预期结果将是通往几个类别的一流路线 阿托品将加快阿托品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.