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Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-14 , DOI: 10.1021/acs.jmedchem.1c01249 Bernard Barlaam 1 , Chris De Savi 2 , Allan Dishington 1 , Lisa Drew 2 , Andrew D Ferguson 3 , Douglas Ferguson 2 , Chungang Gu 2 , Sudhir Hande 2 , Lorraine Hassall 1 , Janet Hawkins 1 , Alexander W Hird 2 , Jane Holmes 1 , Michelle L Lamb 2 , Andrew S Lister 1 , Thomas M McGuire 1 , Jane E Moore 1 , Nichole O'Connell 3 , Anil Patel 1 , Kurt G Pike 1 , Ujjal Sarkar 2 , Wenlin Shao 2 , Darren Stead 1 , Jeffrey G Varnes 2 , Melissa M Vasbinder 2 , Lei Wang 4 , Liangwei Wu 4 , Lin Xue 4 , Bin Yang 2 , Tieguang Yao 4
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-14 , DOI: 10.1021/acs.jmedchem.1c01249 Bernard Barlaam 1 , Chris De Savi 2 , Allan Dishington 1 , Lisa Drew 2 , Andrew D Ferguson 3 , Douglas Ferguson 2 , Chungang Gu 2 , Sudhir Hande 2 , Lorraine Hassall 1 , Janet Hawkins 1 , Alexander W Hird 2 , Jane Holmes 1 , Michelle L Lamb 2 , Andrew S Lister 1 , Thomas M McGuire 1 , Jane E Moore 1 , Nichole O'Connell 3 , Anil Patel 1 , Kurt G Pike 1 , Ujjal Sarkar 2 , Wenlin Shao 2 , Darren Stead 1 , Jeffrey G Varnes 2 , Melissa M Vasbinder 2 , Lei Wang 4 , Liangwei Wu 4 , Lin Xue 4 , Bin Yang 2 , Tieguang Yao 4
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Optimization of a series of azabenzimidazoles identified from screening hit 2 and the information gained from a co-crystal structure of the azabenzimidazole-based lead 6 bound to CDK9 led to the discovery of azaindoles as highly potent and selective CDK9 inhibitors. With the goal of discovering a highly selective and potent CDK9 inhibitor administrated intravenously that would enable transient target engagement of CDK9 for the treatment of hematological malignancies, further optimization focusing on physicochemical and pharmacokinetic properties led to azaindoles 38 and 39. These compounds are highly potent and selective CDK9 inhibitors having short half-lives in rodents, suitable physical properties for intravenous administration, and the potential to achieve profound but transient inhibition of CDK9 in vivo.
中文翻译：
发现一系列 7-氮杂吲哚作为瞬态靶标参与的强效和高选择性 CDK9 抑制剂
从筛选命中2 中鉴定出的一系列氮杂苯并咪唑的优化以及从与 CDK9 结合的基于氮杂苯并咪唑的先导6的共晶结构中获得的信息，导致发现了氮杂吲哚作为高效和选择性的 CDK9 抑制剂。为了发现一种高选择性和有效的 CDK9 抑制剂静脉给药，使 CDK9 能够瞬时靶向参与治疗血液系统恶性肿瘤，进一步优化理化和药代动力学特性导致氮杂吲哚38和39. 这些化合物是高效和选择性的 CDK9 抑制剂，在啮齿动物中具有较短的半衰期，适合静脉内给药的物理特性，并有可能在体内实现对 CDK9 的深刻但短暂的抑制。
更新日期：2021-10-28
中文翻译：
发现一系列 7-氮杂吲哚作为瞬态靶标参与的强效和高选择性 CDK9 抑制剂
从筛选命中2 中鉴定出的一系列氮杂苯并咪唑的优化以及从与 CDK9 结合的基于氮杂苯并咪唑的先导6的共晶结构中获得的信息，导致发现了氮杂吲哚作为高效和选择性的 CDK9 抑制剂。为了发现一种高选择性和有效的 CDK9 抑制剂静脉给药，使 CDK9 能够瞬时靶向参与治疗血液系统恶性肿瘤，进一步优化理化和药代动力学特性导致氮杂吲哚38和39. 这些化合物是高效和选择性的 CDK9 抑制剂，在啮齿动物中具有较短的半衰期，适合静脉内给药的物理特性，并有可能在体内实现对 CDK9 的深刻但短暂的抑制。
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