Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
Chem Rev. 2021 Mar 24;121(6):3297-3351. doi: 10.1021/acs.chemrev.0c00383. Epub 2020 Jul 21.
There has been huge progress in the discovery of targeted cancer therapies in recent years. However, even for the most successful and impactful cancer drugs which have been approved, both innate and acquired mechanisms of resistance are commonplace. These emerging mechanisms of resistance have been studied intensively, which has enabled drug discovery scientists to learn how it may be possible to overcome such resistance in subsequent generations of treatments. In some cases, novel drug candidates have been able to supersede previously approved agents; in other cases they have been used sequentially or in combinations with existing treatments. This review summarizes the current field in terms of the challenges and opportunities that cancer resistance presents to drug discovery scientists, with a focus on small molecule therapeutics. As part of this review, common themes and approaches have been identified which have been utilized to successfully target emerging mechanisms of resistance. This includes the increase in target potency and selectivity, alternative chemical scaffolds, change of mechanism of action (covalents, PROTACs), increases in blood-brain barrier permeability (BBBP), and the targeting of allosteric pockets. Finally, wider approaches are covered such as monoclonal antibodies (mAbs), bispecific antibodies, antibody drug conjugates (ADCs), and combination therapies.
近年来，在发现针对癌症的靶向疗法方面取得了巨大进展。然而，即使是已被批准的最成功和最有影响力的癌症药物，其内在和获得性耐药机制也很常见。这些新出现的耐药机制已得到深入研究，这使药物发现科学家能够了解如何在后续治疗中克服这种耐药性。在某些情况下，新的候选药物能够取代以前批准的药物；在其他情况下，它们被顺序使用或与现有治疗方法联合使用。
本综述总结了癌症耐药性对药物发现科学家提出的挑战和机遇，重点关注小分子治疗药物。作为本综述的一部分，确定了一些常见的主题和方法，这些主题和方法已被成功地用于靶向新出现的耐药机制。这包括提高靶标效力和选择性、替代化学结构、改变作用机制（共价、PROTAC）、增加血脑屏障通透性（BBBP）以及靶向变构口袋。最后，还涵盖了更广泛的方法，如单克隆抗体（mAbs）、双特异性抗体、抗体药物偶联物（ADCs）和联合治疗。
