Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases.,ACS Chemical Neuroscience

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Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-05-28 , DOI: 10.1021/acschemneuro.0c00176
Andrea I Krahn ₁ , Carrow Wells _{2,

3} , David H Drewry _{2,

3} , Lenore K Beitel ₁ , Thomas M Durcan ₁ , Alison D Axtman _{2,

3}

Affiliation

Kinases are highly tractable drug targets that have reached unparalleled success in fields such as cancer but whose potential has not yet been realized in neuroscience. There are currently 55 approved small molecule kinase-targeting drugs, 48 of which have an anticancer indication. The intrinsic complexity linked to central nervous system (CNS) drug development and a lack of validated targets has hindered progress in developing kinase inhibitors for CNS disorders when compared to other therapeutic areas such as oncology. Identification and/or characterization of new kinases as potential drug targets for neurodegenerative diseases will create opportunities for the development of CNS drugs in the future. The track record of kinase inhibitors in other disease indications supports the idea that with the best targets identified small molecule kinase modulators will become impactful therapeutics for neurodegenerative diseases. This Review highlights the imminent need for new therapeutics to treat the most prevalent neurodegenerative diseases as well as the promise of kinase inhibitors to address this need. With a focus on kinases that remain largely unexplored after decades of dedicated research in the kinase field, we offer specific examples of understudied kinases that are supported by patient-derived data as linked to Alzheimer’s disease, Parkinson’s disease, and/or amyotrophic lateral sclerosis. Finally, we show literature-reported high-quality inhibitors for several understudied kinases and suggest other kinases that merit additional medicinal chemistry efforts to elucidate their therapeutic potential.

中文翻译：

定义神经动力学：小分子药物发现针对神经退行性疾病的策略和机会。

激酶是高度易处理的药物靶标，已在癌症等领域取得了无与伦比的成功，但其潜力尚未在神经科学中实现。当前有55种已批准的靶向小分子激酶的药物，其中48种具有抗癌适应症。与其他治疗领域（例如肿瘤学）相比，与中枢神经系统（CNS）药物开发有关的内在复杂性和缺乏经过验证的靶标阻碍了开发CNS疾病激酶抑制剂的进展。作为神经退行性疾病潜在药物靶标的新激酶的鉴定和/或表征将为将来的中枢神经系统药物的开发创造机会。激酶抑制剂在其他疾病适应症中的往绩记录支持以下观点：通过确定最佳靶点，小分子激酶调节剂将成为神经退行性疾病的有效疗法。这篇评论强调了对治疗最普遍的神经退行性疾病的新疗法的迫切需求，以及激酶抑制剂有望满足这一需求的希望。我们专注于在激酶领域数十年专门研究后仍未开发的激酶，我们提供了尚未充分研究的激酶的具体实例，这些实例得到了与阿尔茨海默氏病，帕金森氏病和/或肌萎缩性侧索硬化症相关的患者来源数据的支持。最后，

更新日期：2020-07-01

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