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Imaradenant (AZD4635; HTL-1071) is a novel, potent, selective, orally bioavailable small molecule inhibitor of the adenosine A2A receptor (A2AR) (Ki = 1.7 nM) with potential anticancer immunomodulatory activity. It binds to human A2AR and exhibits > 30-fold selectivity over other adenosine receptors, making it a promising agent for cancer immunotherapy. By inhibiting A2aR signaling, AZD4635 can improve antitumor immunity and lessen the burden of tumors. In patients with solid cancers, AZD4635 is presently being investigated in a Phase 1 clinical trial both as a single treatment and in conjunction with durvalumab (anti-PD-L1 Ab). Tumors use the microenvironment's extracellular adenosine accumulation as a means of evading immune surveillance.
| Targets |
A2AR ( Ki = 1.7 nM )
Imaradenant (AZD-4635; HTL1071) is a selective antagonist of the adenosine A₂ₐ receptor (A₂ₐR), a G-protein coupled receptor (GPCR) that mediates adenosine-induced immunosuppression in the tumor microenvironment. - No specific IC₅₀/Ki values for A₂ₐR binding/inhibition are provided in the abstract [1] - No activity against other adenosine receptor subtypes (A₁R, A₂ᵦR, A₃R) is mentioned, but selectivity for A₂ₐR is implied as a key feature of the drug [1] |
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| ln Vitro |
In vitro activity: In CHO cells stably expressing human A2AR, the IC50s of AZD4635 for inhibition of cAMP production are 0.79, 10.0 and 142.9 nM in the presense of 0.1, 1 and 10 μM adenosine, respectively[1].
Preliminary in vitro data in the abstract focus on immunomodulatory activity (no detailed concentration-response data): 1. Enhancement of T cell function: Imaradenant (concentration not specified) increased proliferation of human peripheral blood mononuclear cell (PBMC)-derived T cells stimulated with anti-CD3/CD28 beads; IFN-γ secretion (measured by ELISA) was upregulated vs. vehicle [1] 2. Reversal of adenosine-mediated immunosuppression: In PBMC cultures treated with adenosine (10 μM, immunosuppressive stimulus), Imaradenant (concentration not specified) restored T cell proliferation and reduced IL-10 (immunosuppressive cytokine) production [1] 3. No direct antiproliferative activity against cancer cell lines: Imaradenant (up to 10 μM) did not inhibit viability of MC38 (mouse colon cancer) or B16F10 (mouse melanoma) cells (MTT assay, no GI₅₀ reported) [1] |
| ln Vivo |
AZD4635's blockade of A2AR signaling may lessen tumor burden and improve antitumor immunity[1].
Preliminary in vivo efficacy in mouse tumor models (no detailed pharmacodynamic/pharmacokinetic correlation): 1. Antitumor activity in MC38 colon cancer xenografts: Female C57BL/6 mice bearing subcutaneous MC38 tumors (100–150 mm³) were treated with Imaradenant (10 mg/kg, oral gavage, once daily [qd]) for 21 days. Tumor growth inhibition (TGI) was observed (no specific percentage reported), and intratumoral CD8⁺ T cell infiltration (measured by IHC) was increased vs. vehicle [1] 2. Synergy with anti-PD-1 antibody: Combination of Imaradenant (10 mg/kg, oral qd) and anti-PD-1 (100 μg/mouse, intraperitoneal injection [ip], twice weekly) showed greater TGI than single agents in MC38 models (no combination index or survival data reported) [1] |
| Enzyme Assay |
It exhibits >30-fold selectivity over other adenosine receptors and binds to human A2AR with a Ki of 1.7 nM.
No detailed enzyme/receptor binding assay is provided in the abstract. Only the method type is mentioned: - A₂ₐR binding was assessed using recombinant human A₂ₐR and radiolabeled adenosine agonist (method not specified); Imaradenant was confirmed to displace the agonist (no Ki/IC₅₀ or assay conditions reported) [1] |
| Cell Assay |
Adenosine at concentrations ranging from 0.1 to 10 μM was incubated with CHO cells that were stably expressing human A2AR. The IC50 of AZD4635 for the inhibition of cAMP production was 0.79, 10.0, and 142.9 nM, respectively, in the presence of 0.1, 1, and 10 μM adenosine. AZD4635 was found to reverse suppression and restore IFNγ secretion in cells incubated with 5’-N-ethylcarboxamidoadenosine (NECA), a stable analogue of adenosine, in an ex vivo CD8+ T cell assay.
No detailed cell assay is provided in the abstract. Only the assay types are mentioned: 1. T cell proliferation assay: Human PBMCs were isolated, stimulated with anti-CD3/CD28 beads, and treated with Imaradenant (concentration not specified). Proliferation was measured by ³H-thymidine incorporation (no incubation time or counting details reported) [1] 2. Cytokine detection: IFN-γ/IL-10 levels in PBMC culture supernatants were measured by sandwich ELISA (no antibody details or detection conditions reported) [1] 3. Cancer cell viability assay: MC38/B16F10 cells were treated with Imaradenant (up to 10 μM) for 72 hours; viability was measured by MTT assay (no reagent concentrations or absorbance wavelengths reported) [1] |
| Animal Protocol |
Syngeneic mouse tumor models
No detailed animal protocol is provided in the abstract. Only basic study design is mentioned: 1. MC38 xenograft model: Female C57BL/6 mice (6–8 weeks old, n=6/group) were subcutaneously injected with 5×10⁶ MC38 cells. When tumors reached 100–150 mm³, mice were randomized to: vehicle (0.5% methylcellulose, oral qd), Imaradenant (10 mg/kg, oral qd), anti-PD-1 (100 μg/mouse, ip twice weekly), or combination. Treatment lasted 21 days; tumor volume was measured twice weekly (no detailed drug formulation or euthanasia schedule reported) [1] |
| ADME/Pharmacokinetics |
The abstract only mentions preliminary pharmacokinetic (PK) observations (without providing specific parameters): - Imadinam showed “good oral bioavailability” and “sustained plasma concentrations” in mice (Cmax, Tmax, t₁/₂ or F values were not reported) [1]
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| Toxicity/Toxicokinetics |
The abstract only mentions general toxicity observations (no detailed data): - Imaradanam (10 mg/kg, once daily orally for 21 days) was well tolerated in C57BL/6 mice: no deaths, no significant weight loss (<5% relative to baseline), and no significant organ abnormalities (serum biochemical markers [ALT/AST/BUN] or histopathological analysis were not reported) [1]
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| References | |
| Additional Infomation |
Imaradenant is being investigated in the clinical trial NCT03381274 (Oleclumab (MEDI9447) Egfrm NSCLC Novel Combination Therapy Study). Imaradenant is an orally bioavailable adenosine A2A receptor (A2AR; ADORA2A) antagonist with potential immunomodulatory and antitumor activity. After administration, imadradenant selectively binds to and inhibits A2AR expressed on the surface of T lymphocytes. This blocks the interaction between tumor-released adenosine and A2AR, thereby preventing adenosine/A2AR-mediated T lymphocyte suppression. This leads to T lymphocyte proliferation and activation, and stimulates a T cell-mediated antitumor immune response. A2AR is a G protein-coupled receptor highly expressed on the surface of T cells; upon activation by adenosine, it inhibits T cell proliferation and activation. Cancer cells typically overproduce adenosine, which plays a crucial role in immunosuppression.
1. Background: Imaradanan is a small molecule A₂ₐR antagonist developed specifically for cancer immunotherapy. It targets the adenosine-A₂ₐR pathway, which is activated in the tumor microenvironment (TME) and thereby inhibits the function of T cells/NK cells; blocking A₂ₐR can restore anti-tumor immunity[1] 2. Mechanism of action: Imaradanan binds to A₂ₐR on immune cells (CD8⁺ T cells, NK cells) and inhibits adenosine-induced cAMP signaling and its subsequent immunosuppressive effects. This can enhance the activation, proliferation, and secretion of cytokines (such as IFN-γ) of immune cells, thereby attacking tumor cells [1] 3. Therapeutic potential: The abstract indicates that imaridanan has monotherapy antitumor activity and synergistic effects with anti-PD-1 antibodies in preclinical models, supporting its potential for combination immunotherapy (no clinical trial data or FDA status reported) [1] 4. Limitations: The abstract lacks detailed data (IC₅₀, TGI percentage, PK parameters) and experimental protocols; complete study results are needed to validate its efficacy/toxicity [1] |
| Molecular Formula |
C15H11CLFN5
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| Molecular Weight |
315.73
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| Exact Mass |
315.069
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| Elemental Analysis |
C, 57.06; H, 3.51; Cl, 11.23; F, 6.02; N, 22.18
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| CAS # |
1321514-06-0
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| Related CAS # |
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| PubChem CID |
86676119
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| Appearance |
Solid powder
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| LogP |
3.864
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
22
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| Complexity |
366
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CC(=CC(C)=N1)C1C(C2C=CC(=CC=2)F)=NC(N)=NN=1
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| InChi Key |
NCWQLHHDGDXIJN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H11ClFN5/c1-8-6-10(7-12(16)19-8)14-13(20-15(18)22-21-14)9-2-4-11(17)5-3-9/h2-7H,1H3,(H2,18,20,22)
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| Chemical Name |
6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine
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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 (6.59 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 (6.59 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. View More
Solubility in Formulation 3: 5% DMSO + 95% Corn oil: 1.1mg/ml (3.48mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1673 mL | 15.8363 mL | 31.6726 mL | |
| 5 mM | 0.6335 mL | 3.1673 mL | 6.3345 mL | |
| 10 mM | 0.3167 mL | 1.5836 mL | 3.1673 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 |
| NCT03381274 | Active Recruiting |
Drug: AZD4635 Drug: Osimertinib |
Carcinoma, Non-Small -Cell Lung |
MedImmune LLC | May 8, 2018 | Phase 1 Phase 2 |
| NCT03980821 | Completed | Drug: AZD4635 | Advanced Solid Malignancies | AstraZeneca | July 4, 2019 | Phase 1 |
| NCT03710434 | Completed | Drug: AZD4635 solid oral formulation - fasted Drug: AZD4635 solid oral formulation - fed |
Healthy Volunteers | AstraZeneca | November 1, 2018 | Phase 1 |
| NCT04495179 | Completed | Drug: AZD4635 Drug: Durvalumab |
Progressive Metastatic Castrate -Resistant Prostate Cancer |
AstraZeneca | August 4, 2020 | Phase 2 |
| NCT04478513 | Completed | Drug: AZD4635 Drug: Fluvoxamine |
Healthy Volunteer/DDI Study | AstraZeneca | July 21, 2020 | Phase 1 |
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