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Purity: ≥98%
AZD4573 (AZD-4573) is a novel, potent and short acting inhibitor of serine/threonine CDK9 (cyclin-dependent kinase 9, IC50<0.004 μM) with potential anticancer activities. It has strong selectivity against other kinases, including those in the CDK family, and fast-off binding kinetics (t1/2 = 16 min). A variety of anti-apoptotic proteins' gene transcription is inhibited when AZD4573 binds to CDK9 and inhibits its phosphorylation and kinase activity. This prevents PTEFb-mediated activation of RNA Pol II.
AZD4573 is a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor designed for intravenous administration. It exerts its anti-tumor effect through transient CDK9 inhibition, indirectly down-regulating key survival proteins such as MCL-1 and inducing tumor cell apoptosis. The compound exhibits nanomolar inhibitory activity against CDK9 and demonstrates >10-fold (and up to >100-fold) selectivity over other CDK family kinases, with fast-off binding kinetics.| Targets |
CDK9 (IC50 = 4 nM); The target of AZD4573 is cyclin-dependent kinase 9 (CDK9). CDK9 is a key regulator of transcription elongation. Forming a complex with cyclin T, it phosphorylates the C-terminal domain of RNA polymerase II (RNAPII) at Serine 2, thereby promoting transcription elongation. AZD4573 selectively inhibits CDK9 activity with an IC50 < 3 nM in biochemical assays. Through transient CDK9 inhibition, AZD4573 rapidly downregulates short-lived mRNAs and proteins, including MCL-1, MYC, BFL-1/A1, JunB, and PIM3.
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| ln Vitro |
AZD4573 treatment for a brief period of time resulted in a fast dose- and time-dependent reduction in cellular pSer2-RNAPII, which in turn activated caspase 3 and induced cell death in a variety of haematological cancer cell lines (for example, caspase activation EC50 13.7 nM in an acute myeloid leukemia model MV4-11) [1].
AZD4573 demonstrates potent anti-proliferative and pro-apoptotic activity across various hematologic cancer cell lines, with a median GI50 of 11 nM and median caspase activation EC50 of 30 nM. In breast cancer cell lines, the IC50 of AZD4573 ranges from 9.16 to 25 nM in sensitive cells. By inhibiting CDK9, AZD4573 reduces RNAPII Ser2 phosphorylation, thereby downregulating anti-apoptotic and oncoproteins such as MCL-1 and MYC. In DLBCL cell lines, the IC50 of AZD4573 ranges from approximately 3-30 nM. Additionally, in high-grade glioma (HGG) and diffuse intrinsic pontine glioma (DIPG) cells, AZD4573 synergizes with radiotherapy to enhance colony formation inhibition. |
| ln Vivo |
AZD4573 has a short half-life (less than an hour in the case of rats, dogs, and monkeys) and is well soluble when administered intravenously[1].
In multiple xenograft models, AZD4573 monotherapy significantly inhibits tumor growth and induces tumor regression. Durable regressions have been observed in subcutaneous and disseminated models of multiple myeloma (MM), acute myeloid leukemia (AML), and non-Hodgkin’s lymphoma (NHL). In a SU-DIPG13* xenograft model, AZD4573 (15 mg/kg, intraperitoneal, twice weekly) combined with radiotherapy significantly prolongs mouse survival. The median survival of the combination group is significantly higher than that of the radiotherapy alone group (p < 0.0001). Furthermore, AZD4573 enhances the anti-tumor activity of venetoclax in AML, MM, and NHL models, as well as the activity of acalabrutinib in NHL cell lines and subcutaneous xenografts. |
| Enzyme Assay |
Kinase Activity Assay: Incubate recombinant human CDK9/cyclin T complex with varying concentrations of AZD4573 in a reaction system.
Substrate and ATP Addition: Add a specific peptide substrate and [γ-³³P]ATP to initiate the phosphorylation reaction, incubate at 30°C for an appropriate duration.
Signal Detection: After terminating the reaction, transfer the mixture to phosphocellulose filters, wash to remove unbound ATP, and measure filter-bound radioactivity using a scintillation counter.
Data Analysis: Plot the concentration-inhibition curve and calculate the IC50 value. Biochemical assay results demonstrate that AZD4573 inhibits CDK9 with an IC50 < 3 nM.
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| Cell Assay |
Cell Culture: Culture tumor cells (e.g., leukemia, lymphoma, breast cancer cell lines) in appropriate plates with medium containing 10% fetal bovine serum at 37°C in a 5% CO₂ incubator.
Drug Treatment: Treat cells with various concentrations of AZD4573 (0.001-10 μM) and incubate for 6-72 hours.
Viability Assay: Assess cell viability using MTT or CellTiter-Glo assays. In hematologic cancer cell lines, the median GI50 of AZD4573 is 11 nM, and the median caspase activation EC50 is 30 nM.
Apoptosis Detection: Detect apoptosis rate using Annexin V-FITC/PI double staining by flow cytometry.
Protein Expression Analysis: Detect changes in RNAPII Ser2 phosphorylation, MCL-1, MYC, and other target proteins by Western blot.
DNA Damage Assessment: Evaluate DNA strand breaks using the alkaline comet assay.
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| Animal Protocol |
Nomo-1 AML xenograft
5 mg/kg i.p. Animals & Models: Establish xenograft models (subcutaneous and disseminated) using immunodeficient mice (e.g., NSG, nude mice) with tumor types including AML, MM, and NHL. Dosing Regimen: Administer AZD4573 via intraperitoneal or intravenous injection, typically at 15 mg/kg twice weekly (biweekly), either alone or in combination with radiotherapy (e.g., 2 Gy × 3 fractions) or other agents (e.g., venetoclax, acalabrutinib). Efficacy Assessment: Measure tumor volume 2-3 times weekly and record survival. In disseminated models, monitor tumor burden via bioluminescent imaging. Pharmacodynamic Detection: Collect tumor tissues or peripheral blood to measure changes in pSer2-RNAPII, MCL-1, and MYC levels. Data Analysis: Calculate tumor growth inhibition rates and compare survival differences using Kaplan-Meier analysis. |
| ADME/Pharmacokinetics |
AZD4573 is suitable for intravenous administration and is designed to achieve transient target engagement. In the Phase 1 first-in-human study, AZD4573 demonstrates dose-proportional pharmacokinetics with linear increases in AUC and Cmax across doses, and moderate PK variability (~30-60% CV). The terminal half-life is approximately 5 hours. Pharmacodynamically, AZD4573 treatment leads to a reduction in pSer2-RNAPII (>75%) and MCL-1 (>70%) in peripheral blood, confirming target engagement and mechanism of action. The recommended Phase 2 dose (RP2D) is 12 mg once weekly for lymphoma and 9 mg once weekly for leukemia.
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| Toxicity/Toxicokinetics |
Based on safety data from the Phase 1 study (NCT03263637), the adverse event profile of AZD4573 is manageable. The most common treatment-related adverse events (TRAEs) include diarrhea (50%), nausea (47.7%), and tumor lysis syndrome (TLS) (40.9%; laboratory TLS 38.6%, clinical TLS 6.8%). Elevated liver enzymes are transient and resolve spontaneously, thought to be primarily due to down-modulation of hepatic transporter proteins leading to reduced drug clearance rather than direct hepatocellular cytotoxicity. Dose-limiting toxicities were observed at the 18 mg dose level, manifesting as clinical TLS and acute kidney injury (Arm A) or hypotension and liver injury (Arm B). No TRAEs led to death. For research use only; handling requires professional supervision.
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| References | |
| Additional Infomation |
Zemirciclib is a selective, short-acting serine/threonine cyclin-dependent kinase 9 (CDK9) inhibitor. CDK9 is the catalytic subunit of positive transcriptional elongation factor b (PTEF-b; PTEFb), an RNA polymerase II (RNA Pol II) elongation factor, and possesses potential antitumor activity. Upon intravenous injection, zemirciclib binds to CDK9 and blocks its phosphorylation and kinase activity, thereby preventing PTEFb-mediated RNA Pol II activation and subsequently inhibiting the transcription of various antiapoptotic proteins. This can induce cell cycle arrest and apoptosis, ultimately leading to reduced tumor cell proliferation. CDK9 regulates transcriptional elongation by phosphorylating the serine 2 site (p-Ser2-RNAPII) of RNA polymerase II. CDK9 is upregulated in various tumor cell types and plays a crucial role in Pol II-mediated transcriptional regulation of antiapoptotic proteins. Tumor cell survival depends on antiapoptotic proteins.
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| Molecular Formula |
C22H28CLN5O2
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| Molecular Weight |
429.9430
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| Exact Mass |
429.19
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| Elemental Analysis |
C, 61.46; H, 6.56; Cl, 8.25; N, 16.29; O, 7.44
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| CAS # |
2057509-72-3
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| Related CAS # |
2057509-72-3;Unknown (HCl);
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| PubChem CID |
124155204
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| Appearance |
White to off-white solid powder
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| LogP |
2.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
30
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| Complexity |
659
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)NC2=NC=C(C(=C2)C3=C4CC(CN4N=C3)(C)C)Cl
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| InChi Key |
AVIWDYSJSPOOAR-LSDHHAIUSA-N
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| InChi Code |
InChI=1S/C22H28ClN5O2/c1-13(29)26-15-6-4-5-14(7-15)21(30)27-20-8-16(18(23)11-24-20)17-10-25-28-12-22(2,3)9-19(17)28/h8,10-11,14-15H,4-7,9,12H2,1-3H3,(H,26,29)(H,24,27,30)/t14-,15+/m0/s1
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| Chemical Name |
(1S,3R)-3-acetamido-N-[5-chloro-4-(5,5-dimethyl-4,6-dihydropyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl]cyclohexane-1-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.84 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.84 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 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 | 1.1630 mL | 2.3259 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05140382 | Active Recruiting |
Drug: AZD4573 | Relapsed/Refractory Peripheral T-cell Lymphoma Relapsed/Refractory Classical Hodgkins Lymphoma |
AstraZeneca | December 15, 2021 | Phase 2 |
| NCT04630756 | Active Recruiting |
Drug: AZD4573 Drug: Acalabrutinib |
Advanced Haematological Malignancies |
AstraZeneca | February 17, 2021 | Phase 1 Phase 2 |
| NCT03263637 | Completed | Drug: AZD4573 | Richter's Syndrome Multiple Myeloma |
AstraZeneca | October 24, 2017 | Phase 1 |
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