Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies

被引：77

作者：

Barlaam, Bernard ^{[1
]}

Casella, Robert ^{[2
]}

Cidado, Justin ^{[3
]}

Cook, Calum ^{[3
,4
]}

De Savi, Chris ^{[3
]}

Dishington, Allan ^{[1
]}

Donald, Craig S. ^{[1
]}

Drew, Lisa ^{[3
]}

Ferguson, Andrew D. ^{[5
]}

Ferguson, Douglas ^{[3
]}

Glossop, Steve ^{[1
]}

Grebe, Tyler ^{[3
]}

Gu, Chungang ^{[3
]}

Hande, Sudhir ^{[3
]}

Hawkins, Janet ^{[1
]}

Hird, Alexander W. ^{[3
]}

Holmes, Jane ^{[1
]}

Horstick, James ^{[3
]}

Jiang, Yun ^{[6
]}

Lamb, Michelle L. ^{[3
]}

McGuire, Thomas M. ^{[1
]}

Moore, Jane E. ^{[1
]}

O'Connell, Nichole ^{[5
]}

Pike, Andy ^{[1
]}

Pike, Kurt G. ^{[1
]}

Proia, Theresa ^{[3
]}

Roberts, Bryan ^{[1
]}

San Martin, Maryann ^{[3
]}

Sarkar, Ujjal ^{[3
]}

Shao, Wenlin ^{[3
]}

Stead, Darren ^{[1
]}

Sumner, Neil ^{[1
]}

Thakur, Kumar ^{[3
]}

Vasbinder, Melissa M. ^{[3
]}

Varnes, Jeffrey G. ^{[3
]}

Wang, Jianyan ^{[2
]}

Wang, Lei ^{[6
]}

Wu, Dedong ^{[2
]}

Wu, Liangwei ^{[6
]}

Yang, Bin ^{[3
]}

Yao, Tieguang ^{[6
]}

机构：

[1] AstraZeneca, Oncol R&D, Cambridge CB4 0WG, England

[2] AstraZeneca, Adv Drug Delivery, Pharmaceut Sci, R&D, Boston, MA 02451 USA

[3] AstraZeneca, Oncol R&D, Boston, MA 02451 USA

[4] AstraZeneca, Oncol R&D, Macclesfield SK10 2NA, Cheshire, England

[5] AstraZeneca, Discovery Sci, Boston, MA 02451 USA

[6] Pharmaron Beijing Co Ltd, Beijing 100176, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 24期

关键词：

KINASE; 9; INHIBITORS; MCL-1; CELL-CYCLE; CANCER; EFFICACY; FAMILY;

D O I：

10.1021/acs.jmedchem.0c01754

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：15564 / 15590

页数：27

共 45 条

[1] Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans [J].

Adelman, Karen ;

Lis, John T. .

NATURE REVIEWS GENETICS, 2012, 13 (10) :720-731

[2] Characterization of molecular and cellular functions of the cyclin-dependent kinase CDK9 using a novel specific inhibitor [J].

Albert, T. K. ;

Rigault, C. ;

Eickhoff, J. ;

Baumgart, K. ;

Antrecht, C. ;

Klebl, B. ;

Mittler, G. ;

Meisterernst, M. .

BRITISH JOURNAL OF PHARMACOLOGY, 2014, 171 (01) :55-68

[3] Imidazoles: SAR and development of a potent class of cyclin-dependent kinase inhibitors [J].

Anderson, Malcolm ;

Andrews, David M. ;

Barker, Andy J. ;

Brassington, Claire A. ;

Breed, Jason ;

Byth, Kate F. ;

Culshaw, Janet D. ;

Finlay, M. Raymond V. ;

Fisher, Eric ;

McMiken, Helen H. J. ;

Green, Clive P. ;

Heaton, Dave W. ;

Nash, Ian A. ;

Newcombe, Nicholas J. ;

Oakes, Sandra E. ;

Pauptit, Richard A. ;

Roberts, Andrew ;

Stanway, Judith J. ;

Thomas, Andrew P. ;

Tucker, Julie A. ;

Walker, Mike ;

Weir, Hazel M. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (20) :5487-5492

[4] Directing cancer cells to self-destruct with pro-apoptotic receptor agonists [J].

Ashkenazi, Avi .

NATURE REVIEWS DRUG DISCOVERY, 2008, 7 (12) :1001-1012

[5] The landscape of somatic copy-number alteration across human cancers [J].

Beroukhim, Rameen ;

Mermel, Craig H. ;

Porter, Dale ;

Wei, Guo ;

Raychaudhuri, Soumya ;

Donovan, Jerry ;

Barretina, Jordi ;

Boehm, Jesse S. ;

Dobson, Jennifer ;

Urashima, Mitsuyoshi ;

Mc Henry, Kevin T. ;

Pinchback, Reid M. ;

Ligon, Azra H. ;

Cho, Yoon-Jae ;

Haery, Leila ;

Greulich, Heidi ;

Reich, Michael ;

Winckler, Wendy ;

Lawrence, Michael S. ;

Weir, Barbara A. ;

Tanaka, Kumiko E. ;

Chiang, Derek Y. ;

Bass, Adam J. ;

Loo, Alice ;

Hoffman, Carter ;

Prensner, John ;

Liefeld, Ted ;

Gao, Qing ;

Yecies, Derek ;

Signoretti, Sabina ;

Maher, Elizabeth ;

Kaye, Frederic J. ;

Sasaki, Hidefumi ;

Tepper, Joel E. ;

Fletcher, Jonathan A. ;

Tabernero, Josep ;

Baselga, Jose ;

Tsao, Ming-Sound ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Janne, Pasi A. ;

Daly, Mark J. ;

Nucera, Carmelo ;

Levine, Ross L. ;

Ebert, Benjamin L. ;

Gabriel, Stacey ;

Rustgi, Anil K. ;

Antonescu, Cristina R. ;

Ladanyi, Marc ;

Letai, Anthony .

NATURE, 2010, 463 (7283) :899-905

[6] MCL1 and BCL-xL Levels in Solid Tumors Are Predictive of Dinaciclib-Induced Apoptosis [J].

Booher, Robert N. ;

Hatch, Harold ;

Dolinski, Brian M. ;

Nguyen, Thi ;

Harmonay, Lauren ;

Al-Assaad, Ali-Samer ;

Ayers, Mark ;

Nebozhyn, Michael ;

Loboda, Andrey ;

Hirsch, Heather A. ;

Zhang, Theresa ;

Shi, Bin ;

Merkel, Carrie E. ;

Angagaw, Minilik H. ;

Wang, Yaolin ;

Long, Brian J. ;

Lennon, Xianlu Q. ;

Miselis, Nathan ;

Pucci, Vincenzo ;

Monahan, James W. ;

Lee, Junghoon ;

Kondic, Anna Georgieva ;

Im, Eun Kyung ;

Mauro, David ;

Blanchard, Rebecca ;

Gilliland, Gary ;

Fawell, Stephen E. ;

Zawel, Leigh ;

Schuller, Alwin G. ;

Strack, Peter .

PLOS ONE, 2014, 9 (10)

[7] Dysregulation of the basal RNA polymerase transcription apparatus in cancer [J].

Bywater, Megan J. ;

Pearson, Richard B. ;

McArthur, Grant A. ;

Hannan, Ross D. .

NATURE REVIEWS CANCER, 2013, 13 (05) :299-314

[8] AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies [J].

Caenepeel, Sean ;

Brown, Sean P. ;

Belmontes, Brian ;

Moody, Gordon ;

Keegan, Kathleen S. ;

Chui, Danny ;

Whittington, Douglas A. ;

Huang, Xin ;

Poppe, Leszek ;

Cheng, Alan C. ;

Cardozom, Mario ;

Houze, Jonathan ;

Li, Yunxiao ;

Lucas, Brian ;

Paras, Nick A. ;

Wang, Xianghong ;

Taygerly, Joshua P. ;

Vimolratana, Marc ;

Zancanella, Manuel ;

Zhu, Liusheng ;

Cajulis, Elaina ;

Osgood, Tao ;

Sun, Jan ;

Damon, Leah ;

Egan, Regina K. ;

Greninger, Patricia ;

McClanaghan, Joseph D. ;

Gong, Jianan ;

Moujalled, Donia ;

Pomilio, Giovanna ;

Beltran, Pedro ;

Benes, Cyril H. ;

Roberts, Andrew W. ;

Huang, David C. ;

Wei, Andrew ;

Canon, Jude ;

Coxon, Angela ;

Hughes, Paul E. .

CANCER DISCOVERY, 2018, 8 (12) :1582-1597

[9] Mcl-1 inhibitors: a patent review [J].

Chen, Lijia ;

Fletcher, Steven .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2017, 27 (02) :163-178

[10] AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells [J].

Cidado, Justin ;

Boiko, Scott ;

Proia, Theresa ;

Ferguson, Douglas ;

Criscione, Steven W. ;

San Martin, Maryann ;

Pop-Damkov, Petar ;

Su, Nancy ;

Franklin, Valar Nila Roamio ;

Chilamakuri, Chandra Sekhar Reddy ;

D'Santos, Clive S. ;

Shao, Wenlin ;

Saeh, Jamal C. ;

Koch, Raphael ;

Weinstock, David M. ;

Zinda, Michael ;

Fawell, Stephen E. ;

Drew, Lisa .

CLINICAL CANCER RESEARCH, 2020, 26 (04) :922-934

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