AZD4573
目录号 : GC32717AZD4573 is a potent inhibitor of CDK9 (IC50 of <0.004 μM) with fast-off binding kinetics (t1/2 = 16 min) and high selectivity versus other kinases, including other CDK family kinases.
Cas No.:2057509-72-3
Sample solution is provided at 25 µL, 10mM.
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AZD4573 is a potent inhibitor of CDK9 (IC50 of <0.004 μM) with fast-off binding kinetics (t1/2 = 16 min) and high selectivity versus other kinases, including other CDK family kinases.
Short-term treatment with AZD4573 leads to a rapid dose- and time-dependent decrease in cellular pSer2-RNAPII, resulting in activation of caspase 3 and cell apoptosis in a broad range of haematological cancer cell lines (e.g. caspase activation EC50 0.0137 μM in an acute myeloid leukemia model MV4-11)[1]. In human cancer cell line panel screens, AZD4573 demonstrates the ability to induce rapid caspase activation (6h) and loss of viability (24h) across a diverse set of hematological cancers (median caspase EC50 = 30 nM, GI50 = 11 nM) but with minimal effect on solid tumors (median EC50 & GI50 >30 μM)[2].
AZD4573 exhibits a short half-life in multiple preclinical species (less than one hour in rat, dog and monkey) and good solubility for intravenous administration[1].
[1] Bernard Barlaam, et al. AACR Cancer Res. 2018, 78(13 Suppl):Abstract nr 1650. [2] Justin Cidado, et al. AACR Cancer Res. 2018, 78(13 Suppl):Abstract nr 310.
Cas No. | 2057509-72-3 | SDF | |
Canonical SMILES | ClC1=CN=C(NC([C@H]2CCC[C@@H](NC(C)=O)C2)=O)C=C1C3=C(CC(C)(C)C4)N4N=C3 | ||
分子式 | C22H28ClN5O2 | 分子量 | 429.94 |
溶解度 | DMSO : ≥ 125 mg/mL (290.74 mM) | 储存条件 | Store at -20°C |
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1 mM | 2.3259 mL | 11.6295 mL | 23.2591 mL |
5 mM | 0.4652 mL | 2.3259 mL | 4.6518 mL |
10 mM | 0.2326 mL | 1.163 mL | 2.3259 mL |
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AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells
Clin Cancer Res 2020 Feb 15;26(4):922-934.PMID:31699827DOI:10.1158/1078-0432.CCR-19-1853.
Purpose: Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and potential therapeutic target for many cancers. Multiple nonselective CDK9 inhibitors have progressed clinically but were limited by a narrow therapeutic window. This work describes a novel, potent, and highly selective CDK9 inhibitor, AZD4573. Experimental design: The antitumor activity of AZD4573 was determined across broad cancer cell line panels in vitro as well as cell line- and patient-derived xenograft models in vivo. Multiple approaches, including integrated transcriptomic and proteomic analyses, loss-of-function pathway interrogation, and pharmacologic comparisons, were employed to further understand the major mechanism driving AZD4573 activity and to establish an exposure/effect relationship. Results: AZD4573 is a highly selective and potent CDK9 inhibitor. It demonstrated rapid induction of apoptosis and subsequent cell death broadly across hematologic cancer models in vitro, and MCL-1 depletion in a dose- and time-dependent manner was identified as a major mechanism through which AZD4573 induces cell death in tumor cells. This pharmacodynamic (PD) response was also observed in vivo, which led to regressions in both subcutaneous tumor xenografts and disseminated models at tolerated doses both as monotherapy or in combination with venetoclax. This understanding of the mechanism, exposure, and antitumor activity of AZD4573 facilitated development of a robust pharmacokinetic/PD/efficacy model used to inform the clinical trial design. Conclusions: Selective targeting of CDK9 enables the indirect inhibition of MCL-1, providing a therapeutic option for MCL-1-dependent diseases. Accordingly, AZD4573 is currently being evaluated in a phase I clinical trial for patients with hematologic malignancies (clinicaltrials.gov identifier: NCT03263637).See related commentary by Alcon et al., p. 761.
Targeting MCL-1 dysregulates cell metabolism and leukemia-stroma interactions and resensitizes acute myeloid leukemia to BCL-2 inhibition
Haematologica 2022 Jan 1;107(1):58-76.PMID:33353284DOI:10.3324/haematol.2020.260331.
MCL-1 and BCL-2 are both frequently overexpressed in acute myeloid leukemia and critical for the survival of acute myeloid leukemia cells and acute myeloid leukemia stem cells. MCL-1 is a key factor in venetoclax resistance. Using genetic and pharmacological approaches, we discovered that MCL-1 regulates leukemia cell bioenergetics and carbohydrate metabolisms, including the TCA cycle, glycolysis and pentose phosphate pathway and modulates cell adhesion proteins and leukemia-stromal interactions. Inhibition of MCL-1 sensitizes to BCL-2 inhibition in acute myeloid leukemia cells and acute myeloid leukemia stem/progenitor cells, including those with intrinsic and acquired resistance to venetoclax through cooperative release of pro-apoptotic BIM, BAX, and BAK from binding to anti-apoptotic BCL-2 proteins and inhibition of cell metabolism and key stromal microenvironmental mechanisms. The combined inhibition of MCL-1 by MCL-1 inhibitor AZD5991 or CDK9 inhibitor AZD4573 and BCL-2 by venetoclax greatly extended survival of mice bearing patient-derived xenografts established from an acute myeloid leukemia patient who acquired resistance to venetoclax/decitabine. These results demonstrate that co-targeting MCL-1 and BCL-2 improves the efficacy of and overcomes preexisting and acquired resistance to BCL-2 inhibition. Activation of metabolomic pathways and leukemia-stroma interactions are newly discovered functions of MCL-1 in acute myeloid leukemia, which are independent from canonical regulation of apoptosis by MCL-1. Our data provide new mechanisms of synergy and rationale for co-targeting MCL-1 and BCL-2 clinically in patients with acute myeloid leukemia and potentially other cancers.
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.PMID:33306391DOI:10.1021/acs.jmedchem.0c01754.
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.
Cyclin-Dependent Kinase 9 Inhibition as a Potential Treatment for Hepatocellular Carcinoma
Oncology 2022;100(11):602-611.PMID:36103810DOI:10.1159/000526978.
Purpose: Composite cyclin-dependent kinase (CDK) inhibition has shown potential as a treatment for hepatocellular carcinoma (HCC) in preclinical studies. We tested whether the specific inhibition of CDK9 was effective against HCC. Methods: The effects of two specific CDK9 inhibitors, BAY1143572 and AZD4573, in HCC cell lines were examined. We tested the in vivo efficacy of CDK9 inhibition in mouse xenograft models of HuH7 human HCC cells and in an orthotopic model of BNL mouse HCC cells. Overexpression and knockdown of CDK9 were performed to confirm the efficacy of CDK9 inhibition. Results: CDK9 inhibitors exhibited potent antiproliferative activities in HCC cells regardless of the levels of c-myc expression while inhibiting the downstream signals of CDK9, such as the phosphorylation of RNA polymerase II. These 2 CDK9 inhibitors induced apoptosis in HCC cells and reduced the expression of antiapoptotic proteins such as myeloid cell leukemia-1 and survivin. In the xenograft studies, mice receiving either CDK9 inhibitor exhibited significantly slower tumor growth than did the mice receiving vehicles. In the orthotopic model, the HCC growth in mice receiving a CDK9 inhibitor also tended to be slower than that in the control group. Overexpression of CDK9 in HuH7 cells reduced the efficacy of both CDK9 inhibitors. Knockdown of CDK9 expression reduced the proliferative activities of HCC cells. Conclusion: We demonstrated the in vitro and in vivo activity of CDK9 inhibition on multiple HCC cell lines. Our data support further clinical development of CDK9 inhibitors as a treatment for HCC.
A New CDK9 Inhibitor on the Block to Treat Hematologic Malignancies
Clin Cancer Res 2020 Feb 15;26(4):761-763.PMID:31843752DOI:10.1158/1078-0432.CCR-19-3670.
CDK9-specific inhibition with AZD4573 impairs cancer-promoting gene expression such as MCL-1 and has been proven effective in hematologic malignancies preclinical models. This new clinical candidate should be further explored in the clinic not only as a monotherapy but also in combination with BH3 mimetics to prevent treatment resistance.See related article by Cidado et al., p. 922.