Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical
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PRECLINICAL STUDIES
Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models Li Wang 1,2 & Chen Hu 1,2 & Aoli Wang 1,3 & Cheng Chen 1,2 & Jiaxin Wu 1,2 & Zongru Jiang 1,2 & Fengming Zou 1,3 & Kailin Yu 1,3 & Hong Wu 1,3 & Juan Liu 1,2 & Wenliang Wang 1,2 & Zuowei Wang 1,2 & Beilei Wang 1,2 & Ziping Qi 1,3 & Qingwang Liu 3,4 & Wenchao Wang 1,3,4 & Lili Li 5 & Jian Ge 5 & Jing Liu 1,3,4 & Qingsong Liu 1,2,3,4,6 Received: 9 August 2019 / Accepted: 11 October 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
Summary Acute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclindependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvocidib and dinaciclib, have shown potent therapeutic effects in clinical trials on AML, the lack of high selectivity for CDK9 and other CDKs has limited their optimal clinical efficacy. Therefore, developing highly selective CDK9 inhibitors is still imperative for the efficacy and safety profile in treating AML. Here, we report a novel highly selective CDK9 inhibitor, JSH-009, which exhibited high potency against CDK9 and displayed great selectivity over 468 kinases/mutants. It also demonstrates impressive in vitro and in vivo antileukemic efficacy in preclinical models of AML, which makes JSH-009 a useful pharmacological tool for elucidating CDK9-mediated transcription and a novel therapeutic candidate for AML. Keywords CDK9 kinase . Transcription addiction . Acute myeloid leukemia
Introduction Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, and the survival rate is extremely low in comparison to that of chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL) [1]. Despite the heterogeneous genetic backgrounds
Li Wang, Chen Hu, Aoli Wang, Cheng Chen and Jiaxin Wu contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-019-00868-3) contains supplementary material, which is available to authorized users. * Jian Ge [email protected] * Jing Liu [email protected] * Qingsong Liu [email protected] Extended author information available on the last page of the article
of AMLs [2], transcriptional addiction has been observed in most cases, as evidenced by their vulnerabilities to the pharmacological inhibition of key transcriptional regulators such as cyclin-dependent kinase 7/9 (CDK7/9) and BRD4 [3, 4]. CDK9 is the catalytic subunit of p-TEFb (positive transcription elongation factor-b) and phosphorylates Ser2 located in the Cterminal repeat domain (CTD) of RNA Pol II [5], which subsequently leads to transcriptional pause release and transcription elongation [6]. Inhibition of CDK9 can block super enhancerassociated productive transcription and reduce the
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