MIRA: Atropisomerism as an inspiration for drug discovery and new chemistry

项目摘要和摘要 获得选择性的小分子抑制剂是药物开发中的一个常见瓶颈。面临的挑战 选择性的例证是激酶抑制剂(KI)，因为在整个动态组中高活性位点的保守具有 阻碍了高选择性KIS的发展。虽然有50多种FDA批准的KIS，但大多数抑制 许多激动酶，导致患者的不良事件，并限制其作为工具化合物的使用。最近，化学家们 已经实现了利用目标的非保守特征来获得选择性的‘选择性过滤器’， 然而，这些方法的通用性是有限的，因为它们依赖于罕见的事件。在过去5年中 我们小组一直在评估阿托品异构症，认为它可能是一种普遍的‘选择性过滤器’。阿托异构体是一种 手性的一种形式，由受阻的围绕键的旋转而产生，其中旋转构象是对映体。 根据对键旋转的阻碍程度，阿托品可以稳定或不稳定的形式存在。 对映体。许多药物以不稳定的阿托异构体存在，但却将其生物靶标结合在阿托异构体中- 具体的方式。我们已经证明了混杂化合物的类似物‘锁定’到一个单一的 阿托品构象具有更好的靶向选择性，并利用这一点获得高度选择性 几种酶的抑制剂。为了了解这种选择性的来源，我们分析了100多个激酶/Small 分子的共晶结构，观察到围绕轴线的二面体构象空间是 通过不同的激酶进行采样，并且我们以前工作中选择性的一个主要驱动因素是前组织 进入一个狭窄的“靶标偏好”构象范围。这导致我们假设目标选择性 可以通过预先组织预期的异构体轴来快速编程到混杂的支架中 转化为特定目标的首选二面体构象。我们正在不同的背景下对此进行评估 药物特权支架，既依赖于也不依赖于稳定的异构体。第二个长的- 我们研究计划的长期目标是开发新的广泛适用的阿托品选择方法学。 这使得能够直接接触到不同类别的与药物相关的阿托品。在过去5年中 我们小组已经开发出了亲核芳香族取代、亲电芳香族取代的反式选择性变体 取代和替代亲核取代，允许对映体选择性地获得各种阿托异构体 支架包括联芳基、杂二芳基、二芳醚和二芳胺。展望未来，我们计划继续这样做 研究并将这些反应性直接扩展到药物支架上，如在AMG-510和 博苏替尼。我们还将扩展我们的阿托品选择工具箱，以包括新的反应，如阿托品选择 环化反应和自由基加成反应。

Project Summary and Abstract Obtaining selective small molecule inhibitors is a common bottleneck in drug discovery. The challenge of selectivity is exemplified by kinase inhibitors (KIs), as high active site conservation across the kinome has hindered the development of highly selective KIs. While there are 50+ FDA approved KIs, the majority inhibit many kinases, leading to adverse events in patients and limiting their use as tool compounds. Recently, chemists have implemented ‘selectivity filters’ that engage non-conserved features of a target to obtain selectivity, however, the generality of these approaches is limited, as they rely on rare occurrences. Over the past 5 years our group has been evaluating atropisomerism as a potentially general ‘selectivity filter’. Atropisomerism is a form of chirality that arises from hindered rotation about a bond where the rotational conformers are enantiomers. Depending on the degree of hindrance to bond rotation, atropisomers can exist as stable or unstable enantiomers. Many drugs exist as unstable atropisomers yet bind their biological targets in an atropisomer- specific manner. We have shown that analogs of promiscuous compounds that are ‘locked’ into a single atropisomeric conformation possess improved target selectivity and have leveraged this to obtain highly selective inhibitors of several kinases. To understand the origin of this selectivity, we analyzed over 100 kinase/small molecule co-crystal structures and observed that the bulk of dihedral conformational space about the axis was sampled by different kinases, and that a major driver of selectivity in our previous work was the preorganization of the axis into a narrow ‘target-preferred’ conformational range. This led us to hypothesize that target selectivity can be rapidly programmed into promiscuous scaffolds via preorganization of a prospective atropisomeric axis into a specific target’s preferred dihedral conformations. We are evaluating this in the context of diverse pharmaceutically privileged scaffolds, both dependent and independent of stable atropisomerism. A second long- term goal of our research program is the development of new broadly applicable atroposelective methodologies that allow for direct access to diverse classes of pharmaceutically relevant atropisomers. Over the past 5 years our group has developed atroposelective variants of nucleophilic aromatic substitution, electrophilic aromatic substitution and vicarious nucleophilic substitution, allowing for enantioselective access to diverse atropisomeric scaffolds including biaryls, heterobiaryls, diarylethers, and diarylamines. Moving forward we plan to continue this work and extend these reactivities directly to pharmaceutical scaffolds such as those seen in AMG-510 and Bosutinib. We will also extend our atroposelective toolbox to include new reactivities such as atroposelective cyclization and radical additions.