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

项目概要和摘要 获得选择性小分子抑制剂是药物发现中的常见瓶颈。的挑战 选择性的例子是激酶抑制剂（KI），因为整个激酶组的高活性位点保守性 阻碍了高选择性KI的发展。虽然有50多个FDA批准的KI，但大多数抑制 许多激酶，导致患者的不良事件并限制其作为工具化合物的用途。最近，化学家 已经实现了“选择性过滤器”，其接合目标的非保守特征以获得选择性， 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。5年来 我们的小组一直在评估阻转异构作为潜在的一般“选择性过滤器”。阻转异构是一种 手性的一种形式，由围绕键的受阻旋转引起，其中旋转构象异构体是对映异构体。 取决于键旋转的阻碍程度，阻转异构体可以稳定或不稳定存在 对映体。许多药物作为不稳定的阻转异构体存在，但以阻转异构体结合其生物靶标- 具体方式。我们已经表明，类似的混杂化合物，是'锁定'到一个单一的， 阻转异构体构象具有改善的靶选择性，并利用这一点获得高选择性的 几种激酶的抑制剂。为了理解这种选择性的起源，我们分析了超过100种激酶/小 分子共晶结构，并观察到，二面角构象空间的大部分轴是 由不同的激酶采样，在我们以前的工作中，选择性的一个主要驱动因素是预组织 轴的一个狭窄的“目标首选”构象范围。这让我们假设目标选择性 可以通过预期阻转异构体轴的预组织快速编程为混杂支架 转化成特定目标的二面角构象我们正在评估这一点的背景下， 药物特权的支架，既依赖于也不依赖于稳定的阻转异构。一秒钟长- 我们的研究计划的长期目标是发展新的广泛适用的atroposelective方法 其允许直接获得不同种类的药学相关阻转异构体。5年来 我们的小组已经开发了亲核芳族取代、亲电芳族 取代和替代亲核取代，允许对映选择性地获得不同阻转异构体 骨架包括联芳基、杂联芳基、二芳基醚和二芳基胺。今后，我们计划继续这样做， 工作并将这些反应性直接扩展到药物支架，如AMG-510中所见， 博舒替尼。我们还将扩展我们的atroposelective工具箱，以包括新的反应性，如atroposelective 环化和自由基加成。

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.