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

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

  • J Med Chem. 2020 Dec 24;63(24):15564-15590. 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
Affiliations

Affiliations

  • 1 Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, United Kingdom.
  • 2 Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Boston, Massachusetts 02451, United States.
  • 3 Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States.
  • 4 Oncology R&D, AstraZeneca, Macclesfield, SK10 2NA, United Kingdom.
  • 5 Discovery Sciences, AstraZeneca, Boston, Massachusetts 02451, United States.
  • 6 Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing, 100176, P. R. China.
PMID: 33306391 DOI: 10.1021/acs.jmedchem.0c01754
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-143584
    99.88%, CDK9 Inhibitor
    CDK