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    DRUG:

    imaradenant (AZD4635)

    i
    Other names: HTL-1071, HTL 1071, AZD4635, AZD-4635, AZD 4635
    Company:
    AstraZeneca, Nxera Pharma
    Drug class:
    Adenosine A2A receptor antagonist
    Related drugs:
    5ms
    Chirality-Guided Optimization of A2A Adenosine Receptor Antagonists for Enhanced Metabolic Stability and Antitumor Efficacy. (PubMed, J Med Chem)
    This approach led to the discovery of (S)-E8, a chiral compound with markedly improved binding affinity, cellular activity, and in vivo potency compared with AZD4635, a Phase II clinical candidate...Mechanistic studies identified CYP1A2 as the primary enzyme driving the metabolic differences among the enantiomers. These findings underscore the value of chirality-guided design in optimizing drug-like properties and reveal CYP1A2's pivotal role in enantioselective metabolism, offering a promising direction for the development of next-generation A2AAR antagonists.
    Journal
    |
    CYP1A2 (Cytochrome P450, family 1, subfamily A, polypeptide 2)
    |
    imaradenant (AZD4635)
    9ms
    Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study (clinicaltrials.gov)
    P1/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: Jul 2025 --> Mar 2026
    Trial completion date
    |
    EGFR (Epidermal growth factor receptor)
    |
    Tagrisso (osimertinib) • oleclumab (MEDI9447) • imaradenant (AZD4635)
    over1year
    Interaction of Purine and its Derivatives with A1, A2-Adenosine Receptors and Vascular Endothelial Growth Factor Receptor-1 (Vegf-R1) as a Therapeutic Alternative to Treat Cancer. (PubMed, Drug Res (Stuttg))
    Besides, adenosine, cgs-15943, rolofylline, cvt-124, wrc-0571, luf-5834, cvt-6883, AZD-4635, cabozantinib, pazopanib, regorafenib, and sorafenib drugs were used as controls...Besides, the inhibition constants (Ki) values for purine and their derivatives 5: , 9: , 10: , 14: , 15: , 16: , and 20: were lower compared with the controls Theoretical data suggest that purine and their derivatives 5: , 9: , 10: , 14: , 15: , 16: , and 20: could produce changes in cancer cell growth through inhibition of A1, A2-adenosine receptors and VEGFR-1 inhibition. These data indicate that these purine derivatives could be a therapeutic alternative to treat some types of cancer.
    Journal
    |
    VEGFA (Vascular endothelial growth factor A) • FLT1 (Fms-related tyrosine kinase 1)
    |
    sorafenib • pazopanib • Cabometyx (cabozantinib tablet) • Stivarga (regorafenib) • imaradenant (AZD4635)
    over1year
    Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study (clinicaltrials.gov)
    P1/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: Jan 2025 --> Jul 2025
    Trial completion date • Combination therapy • Metastases
    |
    EGFR (Epidermal growth factor receptor)
    |
    Tagrisso (osimertinib) • oleclumab (MEDI9447) • imaradenant (AZD4635)
    almost2years
    Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study (clinicaltrials.gov)
    P1/2, N=43, Active, not recruiting, MedImmune LLC | Phase classification: P1b/2 --> P1/2 | Trial completion date: Sep 2024 --> Jan 2025
    Phase classification • Trial completion date • Combination therapy • Metastases
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR T790M negative
    |
    Tagrisso (osimertinib) • oleclumab (MEDI9447) • imaradenant (AZD4635)
    almost2years
    Safety and pharmacokinetics of imaradenant (AZD4635) in Japanese patients with advanced solid malignancies: a phase I, open-label study. (PubMed, Cancer Chemother Pharmacol)
    No new or unexpected safety concerns were identified, and imaradenant had an acceptable safety profile at both 50- and 75-mg QD.
    PK/PD data • Journal • Metastases
    |
    ADORA2A (Adenosine A2a Receptor)
    |
    imaradenant (AZD4635)
    over2years
    Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study (clinicaltrials.gov)
    P1b/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: Jan 2024 --> Sep 2024
    Trial completion date • Combination therapy • Metastases
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR T790M negative
    |
    Tagrisso (osimertinib) • oleclumab (MEDI9447) • imaradenant (AZD4635)
    over2years
    An Open-label, Phase II Study of AZD4635 in Patients With Prostate Cancer (clinicaltrials.gov)
    P2, N=59, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Apr 2023
    Trial completion • Trial completion date
    |
    Imfinzi (durvalumab) • oleclumab (MEDI9447) • imaradenant (AZD4635)
    over2years
    A Phase 1 Clinical Study of AZD4635 in Patients With Advanced Solid Malignancies (clinicaltrials.gov)
    P1, N=313, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Mar 2023
    Trial completion • Trial completion date • Metastases
    |
    EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase)
    |
    EGFR mutation • MSI-H/dMMR • ALK rearrangement
    |
    Imfinzi (durvalumab) • docetaxel • Xtandi (enzalutamide) • abiraterone acetate • oleclumab (MEDI9447) • imaradenant (AZD4635)
    over2years
    Optimizing breast cancer therapy by inhibiting the adenosine receptor and oxygen consumption (AACR 2023)
    In addition, we propose that blocking tumor oxygen consumption using deferiprone (DFP), phenformin (Phen) and metformin (Met) will further enhance A2aR and PD-1/PD-L1 blockade efficacy. Both 4T1-HRE and E0771-HRE demonstrated increased luciferase activity that correlated with increasing doses of CoCl2 in vitro. Future experiments will focus on characterizing the adenosine pathway in vivo in 4T1-HRE and E0771-HRE tumors and examine how drugs that target the adenosine A2AaR receptor (AZD4635), and oxygen consumption (DFP, Phen and Met) influence tumor oxygen consumption in vivo as well as the activation states of immune cells in the tumor microenvironment.
    PD(L)-1 Biomarker • IO biomarker
    |
    CD8 (cluster of differentiation 8) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • IL2RA (Interleukin 2 receptor, alpha) • CD4 (CD4 Molecule) • GZMB (Granzyme B)
    |
    HIF1A expression
    |
    metformin • phenformin • imaradenant (AZD4635)
    over2years
    Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study (clinicaltrials.gov)
    P1b/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: Dec 2022 --> Jan 2024
    Trial completion date • Combination therapy • Metastases
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR T790M negative
    |
    Tagrisso (osimertinib) • oleclumab (MEDI9447) • imaradenant (AZD4635)