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Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-11 , DOI: 10.1021/acs.jmedchem.0c01754
Bernard Barlaam 1 , Robert Casella 2 , Justin Cidado 3 , Calum Cook 4 , Chris De Savi 3 , Allan Dishington 1 , Craig S. Donald 1 , Lisa Drew 3 , Andrew D. Ferguson 5 , Douglas Ferguson 3 , Steve Glossop 1 , Tyler Grebe 3 , Chungang Gu 3 , Sudhir Hande 3 , Janet Hawkins 1 , Alexander W. Hird 3 , Jane Holmes 1 , James Horstick 3 , Yun Jiang 6 , Michelle L. Lamb 3 , Thomas M. McGuire 1 , Jane E. Moore 1 , Nichole O’Connell 5 , Andy Pike 1 , Kurt G. Pike 1 , Theresa Proia 3 , Bryan Roberts 1 , Maryann San Martin 3 , Ujjal Sarkar 3 , Wenlin Shao 3 , Darren Stead 1 , Neil Sumner 1 , Kumar Thakur 3 , Melissa M. Vasbinder 3 , Jeffrey G. Varnes 3 , Jianyan Wang 2 , Lei Wang 6 , Dedong Wu 2 , Liangwei Wu 6 , Bin Yang 3 , Tieguang Yao 6
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-11 , DOI: 10.1021/acs.jmedchem.0c01754
Bernard Barlaam 1 , Robert Casella 2 , Justin Cidado 3 , Calum Cook 4 , Chris De Savi 3 , Allan Dishington 1 , Craig S. Donald 1 , Lisa Drew 3 , Andrew D. Ferguson 5 , Douglas Ferguson 3 , Steve Glossop 1 , Tyler Grebe 3 , Chungang Gu 3 , Sudhir Hande 3 , Janet Hawkins 1 , Alexander W. Hird 3 , Jane Holmes 1 , James Horstick 3 , Yun Jiang 6 , Michelle L. Lamb 3 , Thomas M. McGuire 1 , Jane E. Moore 1 , Nichole O’Connell 5 , Andy Pike 1 , Kurt G. Pike 1 , Theresa Proia 3 , Bryan Roberts 1 , Maryann San Martin 3 , Ujjal Sarkar 3 , Wenlin Shao 3 , Darren Stead 1 , Neil Sumner 1 , Kumar Thakur 3 , Melissa M. Vasbinder 3 , Jeffrey G. Varnes 3 , Jianyan Wang 2 , Lei Wang 6 , Dedong Wu 2 , Liangwei Wu 6 , Bin Yang 3 , Tieguang Yao 6
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A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.
中文翻译：
AZD4573的发现，一种有效的CDK9选择性抑制剂，可在短时间内进行目标靶点治疗血液恶性肿瘤
具有短靶标参与的CDK9抑制剂将使Mcl-1活性降低，从而导致依赖Mcl-1存活的癌细胞凋亡。我们报告了一系列酰胺基吡啶类化合物（来自化合物2）的优化，侧重于适合于在静脉内给药后实现短靶结合的特性。通过提高效力和人类代谢清除率，我们确定了化合物24，这是一种有效的且选择性的CDK9抑制剂，具有适当的预测的人类药代动力学特性，可瞬时抑制CDK9。此外，认为24的溶解度足以允许以预期的有效剂量静脉内配制。化合物24的短期治疗导致pSer2-RNAP2和Mcl-1的剂量和时间依赖性快速下降，导致多种血液癌细胞系中的细胞凋亡。在衍生自多种血液学肿瘤的异种移植模型中，化合物24的间歇给药已证明是有效的。化合物24目前正在临床上用于治疗血液系统恶性肿瘤。
更新日期：2020-12-24
中文翻译：
AZD4573的发现，一种有效的CDK9选择性抑制剂，可在短时间内进行目标靶点治疗血液恶性肿瘤
具有短靶标参与的CDK9抑制剂将使Mcl-1活性降低，从而导致依赖Mcl-1存活的癌细胞凋亡。我们报告了一系列酰胺基吡啶类化合物（来自化合物2）的优化，侧重于适合于在静脉内给药后实现短靶结合的特性。通过提高效力和人类代谢清除率，我们确定了化合物24，这是一种有效的且选择性的CDK9抑制剂，具有适当的预测的人类药代动力学特性，可瞬时抑制CDK9。此外，认为24的溶解度足以允许以预期的有效剂量静脉内配制。化合物24的短期治疗导致pSer2-RNAP2和Mcl-1的剂量和时间依赖性快速下降，导致多种血液癌细胞系中的细胞凋亡。在衍生自多种血液学肿瘤的异种移植模型中，化合物24的间歇给药已证明是有效的。化合物24目前正在临床上用于治疗血液系统恶性肿瘤。
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