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Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-02 , DOI: 10.1021/acs.jmedchem.1c01171
Jason J Marineau 1 , Kristin B Hamman 1 , Shanhu Hu 1 , Sydney Alnemy 1 , Janessa Mihalich 1 , Anzhelika Kabro 2 , Kenneth Matthew Whitmore 2 , Dana K Winter 2 , Stephanie Roy 2 , Stephane Ciblat 2 , Nan Ke 1 , Anneli Savinainen 1 , Ashraf Wilsily 1 , Goran Malojcic 1 , Robert Zahler 1 , Darby Schmidt 1 , Michael J Bradley 1 , Nigel J Waters 1 , Claudio Chuaqui 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-02 , DOI: 10.1021/acs.jmedchem.1c01171
Jason J Marineau 1 , Kristin B Hamman 1 , Shanhu Hu 1 , Sydney Alnemy 1 , Janessa Mihalich 1 , Anzhelika Kabro 2 , Kenneth Matthew Whitmore 2 , Dana K Winter 2 , Stephanie Roy 2 , Stephane Ciblat 2 , Nan Ke 1 , Anneli Savinainen 1 , Ashraf Wilsily 1 , Goran Malojcic 1 , Robert Zahler 1 , Darby Schmidt 1 , Michael J Bradley 1 , Nigel J Waters 1 , Claudio Chuaqui 1
Affiliation
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CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.
中文翻译：
SY-5609 的发现：CDK7 的选择性非共价抑制剂
CDK7 已成为肿瘤学中令人兴奋的靶点，因为它在癌细胞中失调的两个重要过程中发挥作用：细胞周期和转录。本报告描述了SY-5609的发现，这是一种高效（亚 nM CDK7 K d ）、选择性口服 CDK7 抑制剂，已于 2020 年进入临床（ClinicalTrials.gov 标识符：NCT04247126）。利用基于结构的设计来获得高选择性（> 4000倍最接近的脱靶）和缓慢的解离速率结合动力学，这是有效细胞活性所需的。最后，加入氧化膦作为非典型氢键受体有助于提供所需的效力和代谢稳定性。候选药物SY-5609对细胞中的 CDK7 具有有效的抑制作用，并且在剂量低至 2 mg/kg 时，在小鼠异种移植模型中表现出强大的功效。
更新日期：2021-11-02
中文翻译：
SY-5609 的发现：CDK7 的选择性非共价抑制剂
CDK7 已成为肿瘤学中令人兴奋的靶点，因为它在癌细胞中失调的两个重要过程中发挥作用：细胞周期和转录。本报告描述了SY-5609的发现，这是一种高效（亚 nM CDK7 K d ）、选择性口服 CDK7 抑制剂，已于 2020 年进入临床（ClinicalTrials.gov 标识符：NCT04247126）。利用基于结构的设计来获得高选择性（> 4000倍最接近的脱靶）和缓慢的解离速率结合动力学，这是有效细胞活性所需的。最后，加入氧化膦作为非典型氢键受体有助于提供所需的效力和代谢稳定性。候选药物SY-5609对细胞中的 CDK7 具有有效的抑制作用，并且在剂量低至 2 mg/kg 时，在小鼠异种移植模型中表现出强大的功效。
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